43 results on '"Masuda-Suzukake M"'
Search Results
2. Neurodegeneration in frontotemporal lobar degeneration and motor neurone disease associated with expansions in C9orf72 is linked to TDP-43 pathology and not associated with aggregated forms of dipeptide repeat proteins
- Author
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Davidson, Y., Robinson, A. C., Liu, X., Wu, D., Troakes, C., Rollinson, S., Masuda-Suzukake, M., Suzuki, G., Nonaka, T., Shi, J., Tian, J., Hamdalla, H., Ealing, J., Richardson, A., Jones, M., Pickering-Brown, S., Snowden, J. S., Hasegawa, M., and Mann, D. M. A.
- Published
- 2016
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3. Neurodegeneration in frontotemporal lobar degeneration and motor neurone disease associated with expansions in C9orf72 is linked to TDP‐43 pathology and not associated with aggregated forms of dipeptide repeat proteins
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Davidson, Y., Robinson, A. C., Liu, X., Wu, D., Troakes, C., Rollinson, S., Masuda‐Suzukake, M., Suzuki, G., Nonaka, T., Shi, J., Tian, J., Hamdalla, H., Ealing, J., Richardson, A., Jones, M., Pickering‐Brown, S., Snowden, J. S., Hasegawa, M., and Mann, D. M. A.
- Subjects
Inclusion Bodies ,Male ,Neurons ,dipeptide repeat proteins ,DNA Repeat Expansion ,C9orf72 Protein ,Proteins ,Original Articles ,Dipeptides ,Middle Aged ,Immunohistochemistry ,DNA-Binding Proteins ,motor neurone disease ,TDP‐43 ,nervous system ,frontotemporal lobar degeneration ,C9orf72 ,Nerve Degeneration ,Humans ,Original Article ,Female ,Motor Neuron Disease ,Aged - Abstract
Aims A hexanucleotide expansion in C9orf72 is the major genetic cause of inherited behavioural variant Frontotemporal dementia (bvFTD) and motor neurone disease (MND), although the pathological mechanism(s) underlying disease remains uncertain. Methods Using antibodies to poly‐GA, poly‐GP, poly‐GR, poly‐AP and poly‐PR proteins, we examined sections of cerebral cortex, hippocampus, thalamus, cerebellum and spinal cord, from 20 patients with bvFTD and/or MND bearing an expansion in C9orf72 for aggregated deposits of dipeptide repeat proteins (DPR). Results Antibodies to poly‐GA, poly‐GP and poly‐GR detected numerous rounded cytoplasmic inclusions (NCI) within granule cells of hippocampal dentate gyrus and those of the cerebellum, as well as ‘star‐burst’ shaped NCI in pyramidal neurones of CA3/4 region of hippocampus. NCI were uncommon in Purkinje cells, and only very rarely seen in anterior horn cells. Poly‐PA antibody detected occasional NCI within CA3/4 neurones alone, whereas poly‐PR antibody did not identify any NCI but immunostained the nucleus of anterior horn cells, CA3/4 neurones and Purkinje cells, in patients with or without expansion in C9orf72, as well as in normal controls. Poly‐GA antibody generally detected more DPR than poly‐GP, which in turn was greater than poly‐GR. All patients with bvFTD + MND or MND showed plentiful p62/TDP‐43 positive inclusions in remaining anterior horn cells. Conclusion Degeneration and loss of anterior horn cells associated with expansions in C9orf72 occurs in the absence of DPR, and implies that changes involving loss of nuclear staining for and a cytoplasmic aggregation of TDP‐43 are more likely to be the cause of this.
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- 2015
4. Neurodegeneration in frontotemporal lobar degeneration and motor neurone disease associated with expansions inC9orf72is linked to TDP‐43 pathology and not associated with aggregated forms of dipeptide repeat proteins
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Davidson, Y., primary, Robinson, A. C., additional, Liu, X., additional, Wu, D., additional, Troakes, C., additional, Rollinson, S., additional, Masuda‐Suzukake, M., additional, Suzuki, G., additional, Nonaka, T., additional, Shi, J., additional, Tian, J., additional, Hamdalla, H., additional, Ealing, J., additional, Richardson, A., additional, Jones, M., additional, Pickering‐Brown, S., additional, Snowden, J. S., additional, Hasegawa, M., additional, and Mann, D. M. A., additional
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- 2015
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5. Mutation ∆K281 in MAPT causes Pick's disease.
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Schweighauser M, Garringer HJ, Klingstedt T, Nilsson KPR, Masuda-Suzukake M, Murrell JR, Risacher SL, Vidal R, Scheres SHW, Goedert M, Ghetti B, and Newell KL
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- Humans, Silver, tau Proteins genetics, tau Proteins chemistry, Neurons, Mutation genetics, Pick Disease of the Brain genetics, Frontotemporal Dementia genetics
- Abstract
Two siblings with deletion mutation ∆K281 in MAPT developed frontotemporal dementia. At autopsy, numerous inclusions of hyperphosphorylated 3R Tau were present in neurons and glial cells of neocortex and some subcortical regions, including hippocampus, caudate/putamen and globus pallidus. The inclusions were argyrophilic with Bodian silver, but not with Gallyas-Braak silver. They were not labelled by an antibody specific for tau phosphorylated at S262 and/or S356. The inclusions were stained by luminescent conjugated oligothiophene HS-84, but not by bTVBT4. Electron cryo-microscopy revealed that the core of tau filaments was made of residues K254-F378 of 3R Tau and was indistinguishable from that of Pick's disease. We conclude that MAPT mutation ∆K281 causes Pick's disease., (© 2023. The Author(s).)
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- 2023
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6. Development of a novel tau propagation mouse model endogenously expressing 3 and 4 repeat tau isoforms.
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Hosokawa M, Masuda-Suzukake M, Shitara H, Shimozawa A, Suzuki G, Kondo H, Nonaka T, Campbell W, Arai T, and Hasegawa M
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- Animals, Brain pathology, Humans, Mice, Mice, Transgenic, Protein Isoforms genetics, Protein Isoforms metabolism, tau Proteins genetics, tau Proteins metabolism, Alzheimer Disease pathology, Pick Disease of the Brain pathology, Tauopathies metabolism
- Abstract
The phenomenon of 'prion-like propagation' in which aggregates of abnormal amyloid-fibrilized protein propagate between neurons and spread pathology, is attracting attention as a new mechanism in neurodegenerative diseases. There is a strong correlation between the accumulation or spread of abnormal tau aggregates and the clinical symptoms of tauopathies. Microtubule-associated protein tau (MAPT) contains a microtubule-binding domain that consists of three or four repeats (3R/4R) due to alternative mRNA splicing of transcripts for the MAPT gene. Although a number of models for tau propagation have been reported, most use 4R human tau transgenic mice or adult wild-type mice expressing only endogenous 4R tau and these models have not been able to reproduce the pathology of Alzheimer's disease in which 3R and 4R tau accumulate simultaneously, or that of Pick's disease in which only 3R tau is aggregated. These deficiencies may reflect differences between human and rodent tau isoforms in the brain. To overcome this problem, we used genome editing techniques to generate mice that express an equal ratio of endogenous 3R and 4R tau, even after they become adults. We injected these mice with sarkosyl-insoluble fractions derived from the brains of human tauopathy patients such as those afflicted with Alzheimer's disease (3R and 4R tauopathy), corticobasal degeneration (4R tauopathy) or Pick's disease (3R tauopathy). At 8-9 months following intracerebral injection of mice, histopathological and biochemical analyses revealed that the abnormal accumulation of tau was seed-dependent, with 3R and 4R tau in Alzheimer's disease-injected brains, 4R tau only in corticobasal degeneration-injected brains and 3R tau only in Pick disease-injected brains, all of which contained isoforms related to those found in the injected seeds. The injected abnormal tau was seeded, and accumulated at the site of injection and at neural connections, predominantly within the same site. The abnormal tau newly accumulated was found to be endogenous in these mice and to have crossed the species barrier. Of particular importance, Pick's body-like inclusions were observed in Pick's disease-injected mice, and accumulations characteristic of Pick's disease were reproduced, suggesting that we have developed the first model that recapitulates the pathology of Pick's disease. These models are not only useful for elucidating the mechanism of propagation of tau pathology involving both 3R and 4R isoforms, but can also reproduce the pathology of tauopathies, which should lead to the discovery of new therapeutic agents., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2022
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7. Phosphorylation of endogenous α-synuclein induced by extracellular seeds initiates at the pre-synaptic region and spreads to the cell body.
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Awa S, Suzuki G, Masuda-Suzukake M, Nonaka T, Saito M, and Hasegawa M
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- Animals, Axons metabolism, Cells, Cultured, Cerebral Cortex cytology, Disease Models, Animal, Embryo, Mammalian, Humans, Male, Mice, Phosphorylation, Primary Cell Culture, Recombinant Proteins administration & dosage, Recombinant Proteins genetics, Recombinant Proteins isolation & purification, Recombinant Proteins metabolism, Synapses metabolism, alpha-Synuclein administration & dosage, alpha-Synuclein genetics, alpha-Synuclein isolation & purification, Hippocampus pathology, Neurodegenerative Diseases pathology, Synapses pathology, alpha-Synuclein metabolism
- Abstract
Accumulation of phosphorylated α-synuclein aggregates has been implicated in several diseases, such as Parkinson's disease (PD) and dementia with Lewy bodies (DLB), and is thought to spread in a prion-like manner. Elucidating the mechanisms of prion-like transmission of α-synuclein is important for the development of therapies for these diseases, but little is known about the details. Here, we injected α-synuclein fibrils into the brains of wild-type mice and examined the early phase of the induction of phosphorylated α-synuclein accumulation. We found that phosphorylated α-synuclein appeared within a few days after the intracerebral injection. It was observed initially in presynaptic regions and subsequently extended its localization to axons and cell bodies. These results suggest that extracellular α-synuclein fibrils are taken up into the presynaptic region and seed-dependently convert the endogenous normal α-synuclein that is abundant there to an abnormal phosphorylated form, which is then transported through the axon to the cell body., (© 2022. The Author(s).)
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- 2022
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8. Assembly of α-synuclein and neurodegeneration in the central nervous system of heterozygous M83 mice following the peripheral administration of α-synuclein seeds.
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Macdonald JA, Chen JL, Masuda-Suzukake M, Schweighauser M, Jaunmuktane Z, Warner T, Holton JL, Grossman A, Berks R, Lavenir I, and Goedert M
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- Aged, Animals, Animals, Genetically Modified, Hindlimb, Humans, Immunohistochemistry, Male, Mice, Neurologic Mutants, Microglia pathology, Motor Neurons pathology, Movement Disorders pathology, Multiple System Atrophy pathology, Mutation, Neurodegenerative Diseases chemically induced, Neurons metabolism, Paralysis chemically induced, Paralysis pathology, alpha-Synuclein administration & dosage, Mice, Neurodegenerative Diseases pathology, alpha-Synuclein metabolism, alpha-Synuclein pharmacology
- Abstract
Peripheral administration (oral, intranasal, intraperitoneal, intravenous) of assembled A53T α-synuclein induced synucleinopathy in heterozygous mice transgenic for human mutant A53T α-synuclein (line M83). The same was the case when cerebellar extracts from a case of multiple system atrophy with type II α-synuclein filaments were administered intraperitoneally, intravenously or intramuscularly. We observed abundant immunoreactivity for pS129 α-synuclein in nerve cells and severe motor impairment, resulting in hindlimb paralysis and shortened lifespan. Filaments immunoreactive for pS129 α-synuclein were in evidence. A 70% loss of motor neurons was present five months after an intraperitoneal injection of assembled A53T α-synuclein or cerebellar extract with type II α-synuclein filaments from an individual with a neuropathologically confirmed diagnosis of multiple system atrophy. Microglial cells changed from a predominantly ramified to a dystrophic appearance. Taken together, these findings establish a close relationship between the formation of α-synuclein inclusions in nerve cells and neurodegeneration, accompanied by a shift in microglial cell morphology. Propagation of α-synuclein inclusions depended on the characteristics of both seeds and transgenically expressed protein., (© 2021. The Author(s).)
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- 2021
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9. Progression of phosphorylated α-synuclein in Macaca fuscata.
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Kawakami I, Motoda A, Hashimoto M, Shimozawa A, Masuda-Suzukake M, Ohtani R, Takase M, Kumashiro M, Samejima K, and Hasegawa M
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- Animals, Inclusion Bodies pathology, Macaca fuscata, Male, Parkinson Disease metabolism, Parkinson Disease pathology, Putamen metabolism, Substantia Nigra metabolism, Substantia Nigra pathology, Synucleinopathies pathology, Brain pathology, Lewy Bodies pathology, Synucleinopathies metabolism, alpha-Synuclein metabolism
- Abstract
Prion-like spreading of abnormal proteins is proposed to occur in neurodegenerative diseases, and the progression of α-synuclein (α-syn) deposits has been reported in the brains of animal models injected with synthetic α-syn fibrils or pathological α-syn prepared from patients with Parkinson's disease (PD) and dementia with Lewy bodies (DLB). However, α-syn transmission in nonhuman primates, which are more similar to humans, has not been fully clarified. Here, we injected synthetic human α-syn fibrils into the left striatum of a macaque monkey (Macaca fuscata). At 3 months after the injection, we examined neurodegeneration and α-syn pathology in the brain using α-syn epitope-specific antibodies, antiphosphorylated α-syn antibodies (pSyn#64 and pSer129), anti-ubiquitin antibodies, and anti-p62 antibodies. Immunohistochemical examination with pSyn#64, pSer129, and α-syn epitope-specific antibodies revealed Lewy bodies, massive α-syn-positive neuronal intracytoplasmic inclusions (NCIs), and neurites in the left putamen. These inclusions were also positive for ubiquitin and p62. LB509, a human-specific α-syn antibody targeting amino acid residues 115-122, showed limited immunoreactivity around the injection site. The left substantia nigra (SN) and the bilateral frontal cortex also contained some NCIs and neurites. The left hemisphere, including parietal/temporal cortex presented sparse α-syn pathology, and no immunoreactivity was seen in olfactory nerves, amygdala, hippocampus, or right parietal/temporal cortex. Neuronal loss and gliosis in regions with α-syn pathology were mild, except for the left striatum and SN. Our results indicate that abnormal α-syn fibrils propagate throughout the brain of M. fuscata via projection, association, and commissural fibers, though the progression of α-syn pathology is limited., (© 2021 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology.)
- Published
- 2021
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10. Common Marmoset Model of α-Synuclein Propagation.
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Masuda-Suzukake M, Shimozawa A, Hashimoto M, and Hasegawa M
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- Amino Acid Sequence, Animals, Brain metabolism, Brain pathology, Callithrix, Disease Models, Animal, Phosphorylation physiology, Synucleinopathies metabolism, Synucleinopathies pathology, alpha-Synuclein metabolism
- Abstract
The propagation of assembled α-synuclein (αS) is key to understanding the pathological mechanisms of synucleinopathies such as Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy.Here we describe a nonhuman primate model of αS propagation using common marmosets (Callithrix jacchus) with an intracerebral injection of synthetic preformed αS fibrils. This protocol enables observation of the formation of phosphorylated αS pathology and its propagation three months after the injection.
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- 2021
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11. Dextran sulphate-induced tau assemblies cause endogenous tau aggregation and propagation in wild-type mice.
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Masuda-Suzukake M, Suzuki G, Hosokawa M, Nonaka T, Goedert M, and Hasegawa M
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Accumulation of assembled tau protein in the central nervous system is characteristic of Alzheimer's disease and several other neurodegenerative diseases, called tauopathies. Recent studies have revealed that propagation of assembled tau is key to understanding the pathological mechanisms of these diseases. Mouse models of tau propagation are established by injecting human-derived tau seeds intracerebrally; nevertheless, these have a limitation in terms of regulation of availability. To date, no study has shown that synthetic assembled tau induce tau propagation in non-transgenic mice. Here we confirm that dextran sulphate, a sulphated glycosaminoglycan, induces the assembly of recombinant tau protein into filaments in vitro . As compared to tau filaments induced by heparin, those induced by dextran sulphate showed higher thioflavin T fluorescence and lower resistance to guanidine hydrochloride, which suggests that the two types of filaments have distinct conformational features. Unlike other synthetic filament seeds, intracerebral injection of dextran sulphate-induced assemblies of recombinant tau caused aggregation of endogenous murine tau in wild-type mice. AT8-positive tau was present at the injection site 1 month after injection, from where it spread to anatomically connected regions. Induced tau assemblies were also stained by anti-tau antibodies AT100, AT180, 12E8, PHF1, anti-pS396 and anti-pS422. They were thioflavin- and Gallyas-Braak silver-positive, indicative of amyloid. In biochemical analyses, accumulated sarkosyl-insoluble and hyperphosphorylated tau was observed in the injected mice. In conclusion, we revealed that intracerebral injection of synthetic full-length wild-type tau seeds prepared in the presence of dextran sulphate caused tau propagation in non-transgenic mice. These findings establish that propagation of tau assemblies does not require tau to be either mutant and/or overexpressed., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain.)
- Published
- 2020
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12. α-Synuclein filaments from transgenic mouse and human synucleinopathy-containing brains are major seed-competent species.
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Morgan SA, Lavenir I, Fan J, Masuda-Suzukake M, Passarella D, DeTure MA, Dickson DW, Ghetti B, and Goedert M
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- Animals, Brain pathology, HEK293 Cells, Homozygote, Humans, Mice, Mice, Transgenic, Synucleinopathies genetics, Synucleinopathies pathology, Brain metabolism, Synucleinopathies metabolism, alpha-Synuclein chemistry, alpha-Synuclein metabolism
- Abstract
Assembled α-synuclein in nerve cells and glial cells is the defining pathological feature of neurodegenerative diseases called synucleinopathies. Seeds of α-synuclein can induce the assembly of monomeric protein. Here, we used sucrose gradient centrifugation and transiently transfected HEK 293T cells to identify the species of α-synuclein from the brains of homozygous, symptomatic mice transgenic for human mutant A53T α-synuclein (line M83) that seed aggregation. The most potent fractions contained Sarkosyl-insoluble assemblies enriched in filaments. We also analyzed six cases of idiopathic Parkinson's disease (PD), one case of familial PD, and six cases of multiple system atrophy (MSA) for their ability to induce α-synuclein aggregation. The MSA samples were more potent than those of idiopathic PD in seeding aggregation. We found that following sucrose gradient centrifugation, the most seed-competent fractions from PD and MSA brains are those that contain Sarkosyl-insoluble α-synuclein. The fractions differed between PD and MSA, consistent with the presence of distinct conformers of assembled α-synuclein in these different samples. We conclude that α-synuclein filaments are the main driving force for amplification and propagation of pathology in synucleinopathies., (© 2020 Morgan et al.)
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- 2020
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13. Silver staining (Campbell-Switzer) of neuronal α-synuclein assemblies induced by multiple system atrophy and Parkinson's disease brain extracts in transgenic mice.
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Lavenir I, Passarella D, Masuda-Suzukake M, Curry A, Holton JL, Ghetti B, and Goedert M
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- Animals, Brain Chemistry genetics, Humans, Mice, Mice, Transgenic, Multiple System Atrophy genetics, Neurons chemistry, Parkinson Disease genetics, Stereotaxic Techniques, alpha-Synuclein administration & dosage, alpha-Synuclein toxicity, Brain pathology, Multiple System Atrophy pathology, Neurons pathology, Parkinson Disease pathology, Silver Staining methods, alpha-Synuclein analysis
- Abstract
Synucleinopathies [Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA)] share filamentous α-synuclein assemblies in nerve cells and glial cells. We compared the abilities of brain extracts from MSA and PD patients to induce neuronal α-synuclein assembly and neurodegeneration following intracerebral injection in heterozygous mice transgenic for human mutant A53T α-synuclein. MSA extracts were more potent than PD extracts in inducing α-synuclein assembly and in causing neurodegeneration. MSA assemblies were Campbell-Switzer- and Gallyas-silver-positive, whereas PD assemblies were only Campbell-Switzer-positive, in confirmation of previous findings. However, induced α-synuclein inclusions were invariably Campbell-Switzer-positive and Gallyas-negative, irrespective of whether MSA or PD brain extracts were injected. The α-synuclein inclusions of non-injected homozygous mice transgenic for A53T α-synuclein were also Campbell-Switzer-positive and Gallyas-negative. These findings demonstrate that transgene expression and its intracellular environment dominated over the silver staining properties of the conformers of assembled α-synuclein.
- Published
- 2019
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14. [Prion-like Propagation of Pathological α-Synuclein in Vivo].
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Masuda-Suzukake M and Hasegawa M
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- Animals, Brain metabolism, Callithrix, Humans, Lewy Body Disease, Mice, Neurodegenerative Diseases etiology, Parkinson Disease, Phosphorylation, Prions, Neurodegenerative Diseases metabolism, Protein Aggregation, Pathological, alpha-Synuclein metabolism
- Abstract
α-Synuclein (αS) is the major component of the filamentous inclusions that constitute the defining characteristic of neurodegenerative synucleinopathies, including Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. αS is deposited in a hyperphosphorylated and ubiquitinated form with a β-sheet-rich fibrillar structure in diseased brains. In 2008, some researchers reported that embryonic neurons transplanted into Parkinson's disease brains had Lewy body-like pathologies, suggesting that pathological αS propagates from diseased neurons to young neurons. Subsequently, a growing body of evidence supported the cell-to-cell spread of αS pathologies. Recent studies have revealed that intracerebral injection of insoluble αS into wild-type mice can induce prion-like propagation of phosphorylated αS pathology even 1 month after injection, while injection into αS-knockout mice failed to induce any pathology. We also showed that intracerebral injection of insoluble αS into adult common marmoset brains results in the spreading of abundant αS pathology. These in vivo experiments clearly indicate that insoluble αS has prion-like properties and that it propagates through neural networks. The underlying mechanisms of αS propagation are still poorly understood, but αS propagation model animals could be helpful in elucidating the pathogenetic mechanisms and developing drugs for synucleinopathies.
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- 2019
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15. [Animal models of synucleinopathies: prion-like propagation of alpha-synuclein in wild-type animals].
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Masuda-Suzukake M
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- Animals, Brain physiopathology, Mice, Mice, Knockout, Models, Animal, Prions, Synucleinopathies pathology, alpha-Synuclein chemistry
- Abstract
Accumulation of insoluble alpha-synuclein (αS) is a pathological hallmark of some progressive neurodegenerative diseases including Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy, collectively termed synucleinopathies. In diseased brain, αS forms β-sheet-rich amyloid fibrils and it is accumulated in neurons or glial cells. A growing body of evidence suggests that spreading of αS pathology occur by prion-like propagation mechanisms. Our study revealed that intracerebral injection of synthetic αS amyloid fibrils into wild-type mice induced prion-like propagation of αS pathology at 1 month post injection, while injection of soluble αS did not induce αS pathology. Furthermore, injection of αS amyloid fibrils into αS knockout mice failed to induce any pathologies. We also have demonstrated that intracerebral injection of αS amyloid fibrils into small primates, adult common marmosets, resulted in spreading of αS pathologies and loss of TH-positive neurons. These in vivo experiments clearly indicate that αS amyloid fibrils has prion-like properties and it propagates through neural networks. The underlying mechanisms of αS propagation are poorly understood, however, αS propagation model animals would be useful in elucidating pathogenetic mechanisms and developing disease-modifying drugs for sporadic synucleinopathies.
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- 2019
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16. C9ORF72 dipeptide repeat poly-GA inclusions promote intracellular aggregation of phosphorylated TDP-43.
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Nonaka T, Masuda-Suzukake M, Hosokawa M, Shimozawa A, Hirai S, Okado H, and Hasegawa M
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- Amyotrophic Lateral Sclerosis genetics, Amyotrophic Lateral Sclerosis pathology, Cells, Cultured, DNA Repeat Expansion, Dipeptides genetics, Dipeptides metabolism, Frontotemporal Lobar Degeneration genetics, Frontotemporal Lobar Degeneration pathology, Humans, Phosphorylation, Polyglutamic Acid metabolism, Repetitive Sequences, Amino Acid, alpha-Synuclein metabolism, tau Proteins metabolism, C9orf72 Protein genetics, C9orf72 Protein metabolism, DNA-Binding Proteins metabolism
- Abstract
Amyotrophic lateral sclerosis and frontotemporal lobar degeneration are neurodegenerative diseases characterized by accumulation of insoluble aggregates of phosphorylated 43 kDa TAR DNA-binding protein (TDP-43) and linked with abnormal expansion of a hexanucleotide repeat in an intron of chromosome 9 open reading frame 72 (C9ORF72). However, the relationship between C9ORF72 mutations and TDP-43 aggregation remains unknown. Non-ATG-dependent translation of C9ORF72 repeats produces dipeptide repeat proteins, which form p62-positive aggregates in cerebral cortex and cerebellum of patients. Here, we show that the formation of poly-GA protein inclusions induced intracellular aggregation of endogenous and exogenous TDP-43 in cultured cells. Poly-GA aggregation preceded accumulation of phosphorylated TDP-43. These inclusions induced intracellular aggregation of phosphorylated TDP-43, but not tau or α-synuclein. Formation of phosphorylated TDP-43 aggregates depends on the number of poly-GA repeats. Detergent-insoluble fraction from cells co-expressing poly-GA and TDP-43 could function as seeds for further TDP-43 aggregation. These findings suggest a novel pathogenic mechanism that poly-GA protein aggregation directly promotes pathogenic changes of TDP-43 without the formation of nuclear RNA foci containing GGGGCC repeat expansion or loss-of-function of the C9ORF72 protein., (© The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2018
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17. Ubiquitination of alpha-synuclein filaments by Nedd4 ligases.
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Mund T, Masuda-Suzukake M, Goedert M, and Pelham HR
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- HEK293 Cells, HeLa Cells, Humans, Protein Binding, Ubiquitination genetics, Ubiquitination physiology, Nedd4 Ubiquitin Protein Ligases metabolism, alpha-Synuclein metabolism
- Abstract
Alpha-synuclein can form beta-sheet filaments, the accumulation of which plays a key role in the development of Parkinson's disease, dementia with Lewy bodies and multiple system atrophy. It has previously been shown that alpha-synuclein is a substrate for the HECT domain-containing ubiquitin ligase Nedd4, and is subject to ubiquitin-mediated endosomal degradation. We show here that alpha-synuclein filaments are much better substrates for ubiquitination in vitro than monomeric alpha-synuclein, and that this increased susceptibility cannot be mimicked by the mere clustering of monomers. Recognition by Nedd4 family enzymes is not through the conventional binding of PPxY-containing sequences to WW domains of the ligase, but it also involves C2 and HECT domains. The disease-causing alpha-synuclein mutant A53T is a much less efficient substrate for Nedd4 ligases than the wild-type protein. We suggest that preferential recognition, ubiquitination and degradation of beta-sheet-containing filaments may help to limit toxicity, and that A53T alpha-synuclein may be more toxic, at least in part because it avoids this fate., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2018
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18. Involvement of Cellular Prion Protein in α-Synuclein Transport in Neurons.
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Urrea L, Segura-Feliu M, Masuda-Suzukake M, Hervera A, Pedraz L, García Aznar JM, Vila M, Samitier J, Torrents E, Ferrer I, Gavín R, Hagesawa M, and Del Río JA
- Subjects
- Animals, Cells, Cultured, HEK293 Cells, Humans, Male, Mice, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Transgenic, Prion Proteins genetics, Prion Proteins metabolism, Protein Transport physiology, Neurons metabolism, PrPC Proteins genetics, PrPC Proteins metabolism, alpha-Synuclein genetics, alpha-Synuclein metabolism
- Abstract
The cellular prion protein, encoded by the gene Prnp, has been reported to be a receptor of β-amyloid. Their interaction is mandatory for neurotoxic effects of β-amyloid oligomers. In this study, we aimed to explore whether the cellular prion protein participates in the spreading of α-synuclein. Results demonstrate that Prnp expression is not mandatory for α-synuclein spreading. However, although the pathological spreading of α-synuclein can take place in the absence of Prnp, α-synuclein expanded faster in PrP
C -overexpressing mice. In addition, α-synuclein binds strongly on PrPC -expressing cells, suggesting a role in modulating the effect of α-synuclein fibrils.- Published
- 2018
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19. Erratum to: Involvement of Cellular Prion Protein in α-Synuclein Transport in Neurons.
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Urrea L, Segura-Feliu M, Masuda-Suzukake M, Hervera A, Pedraz L, García-Aznar JM, Vila M, Samitier J, Torrents E, Ferrer I, Gavín R, Hagesawa M, and Del Río JA
- Published
- 2018
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20. Molecular mechanisms of the co-deposition of multiple pathological proteins in neurodegenerative diseases.
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Nonaka T, Masuda-Suzukake M, and Hasegawa M
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- Brain pathology, Humans, Inclusion Bodies metabolism, Neurodegenerative Diseases metabolism, DNA-Binding Proteins metabolism, Inclusion Bodies pathology, Neurodegenerative Diseases pathology, alpha-Synuclein metabolism, tau Proteins metabolism
- Abstract
Intracellular inclusions composed of abnormal protein aggregates are one of the neuropathological features of neurodegenerative diseases, and the formation of intracellular aggregates is believed to be associated with neurodegeneration leading to the onset of these diseases. In typical or pure cases, characteristic pathologies with one particular protein, such as tau, alpha-synuclein or trans-activation response DNA protein 43 (TDP-43), can be observed in brains of patients. On the other hand, multiple protein pathologies co-exist in many cases, raising the possibility that they may influence each other reciprocally in the pathogenesis and progression of the diseases. However, the molecular mechanisms through which these proteins interact with each other and through which they are co-deposited in brains of patients remain poorly understood. In this review, we focus on the mechanisms of deposition of multiple pathological proteins, such as tau, alpha-synuclein and/or TDP-43, and on co-deposition models of these proteins in vitro and in vivo intended to recapitulate the multiple pathologies found in diseased brains., (© 2017 Japanese Society of Neuropathology.)
- Published
- 2018
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21. Prion-like mechanisms and potential therapeutic targets in neurodegenerative disorders.
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Hasegawa M, Nonaka T, and Masuda-Suzukake M
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- Alzheimer Disease physiopathology, Alzheimer Disease therapy, Amyotrophic Lateral Sclerosis physiopathology, Amyotrophic Lateral Sclerosis therapy, Animals, DNA-Binding Proteins metabolism, Disease Progression, Humans, Neurodegenerative Diseases therapy, Parkinson Disease physiopathology, Parkinson Disease therapy, alpha-Synuclein metabolism, tau Proteins metabolism, Neurodegenerative Diseases physiopathology, Prions metabolism
- Abstract
Prion-like propagation of abnormal intracytoplasmic proteins, which are the defining features of major neurodegenerative disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), has been proposed. A growing body of evidence strongly suggests that abnormal tau, α-synuclein and TDP-43 have prion-like properties, convert the corresponding normal proteins into abnormal forms, and are transmitted from cell to cell, spreading throughout the brain. This idea is extremely important not only for understanding the pathogenesis and progression of these diseases, but also for the development of molecular therapies. Since the distributions and spreading of the abnormal proteins are closely associated with disease symptoms and progression, gain-of-toxic-function of these proteins may affect the neurons and glial cells either directly or indirectly, or both. It is essential to regulate the aggregation of abnormal intracellular proteins and their cell-to-cell transmission in order to stop, or at least slow, the progression of these diseases., (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Published
- 2017
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22. Propagation of pathological α-synuclein in marmoset brain.
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Shimozawa A, Ono M, Takahara D, Tarutani A, Imura S, Masuda-Suzukake M, Higuchi M, Yanai K, Hisanaga SI, and Hasegawa M
- Subjects
- Animals, Benzothiazoles, Callithrix, Female, Immunohistochemistry, Lewy Bodies metabolism, Lewy Bodies pathology, Microglia metabolism, Microglia pathology, Nerve Degeneration metabolism, Nerve Degeneration pathology, Neurons metabolism, Neurons pathology, Parkinsonian Disorders metabolism, Parkinsonian Disorders pathology, Recombinant Proteins administration & dosage, Recombinant Proteins metabolism, Sequence Homology, Amino Acid, Thiazoles metabolism, Tyrosine 3-Monooxygenase metabolism, alpha-Synuclein administration & dosage, alpha-Synuclein genetics, Brain metabolism, Brain pathology, Protein Aggregation, Pathological metabolism, Protein Aggregation, Pathological pathology, alpha-Synuclein metabolism
- Abstract
α-Synuclein is a defining, key component of Lewy bodies and Lewy neurites in Parkinson's disease (PD) and dementia with Lewy bodies (DLB), as well as glial cytoplasmic inclusions in multiple system atrophy (MSA). The distribution and spreading of these pathologies are closely correlated with disease progression. Recent studies have revealed that intracerebral injection of synthetic α-synuclein fibrils or pathological α-synuclein prepared from DLB or MSA brains into wild-type or transgenic animal brains induced prion-like propagation of phosphorylated α-synuclein pathology. The common marmoset is a very small primate that is expected to be a useful model of human diseases. Here, we show that intracerebral injection of synthetic α-synuclein fibrils into adult wild-type marmoset brains (caudate nucleus and/or putamen) resulted in spreading of abundant α-synuclein pathologies, which were positive for various antibodies to α-synuclein, including phospho Ser129-specific antibody, anti-ubiquitin and anti-p62 antibodies, at three months after injection. Remarkably, robust Lewy body-like inclusions were formed in tyrosine hydroxylase (TH)-positive neurons in these marmosets, strongly suggesting the retrograde spreading of abnormal α-synuclein from striatum to substantia nigra. Moreover, a significant decrease in the numbers of TH-positive neurons was observed in the injection-side of the brain, where α-synuclein inclusions were deposited. Furthermore, most of the α-synuclein inclusions were positive for 1-fluoro-2,5-bis (3-carboxy-4-hydroxystyryl) benzene (FSB) and thioflavin-S, which are dyes widely used to visualize the presence of amyloid. Thus, injection of synthetic α-synuclein fibrils into brains of non-transgenic primates induced PD-like α-synuclein pathologies within only 3 months after injection. Finally, we provide evidence indicating that neurons with abnormal α-synuclein inclusions may be cleared by microglial cells. This is the first marmoset model for α-synuclein propagation. It should be helpful in studies to elucidate mechanisms of disease progression and in development and evaluation of disease-modifying drugs for α-synucleinopathies.
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- 2017
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23. Like prions: the propagation of aggregated tau and α-synuclein in neurodegeneration.
- Author
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Goedert M, Masuda-Suzukake M, and Falcon B
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- Animals, Humans, Neurodegenerative Diseases metabolism, Neurodegenerative Diseases physiopathology, Prion Proteins metabolism, Protein Aggregation, Pathological, alpha-Synuclein metabolism, tau Proteins metabolism
- Abstract
The abnormal aggregation of a small number of known proteins underlies the most common human neurodegenerative diseases. In tauopathies and synucleinopathies, the normally soluble intracellular proteins tau and α-synuclein become insoluble and filamentous. In recent years, non-cell autonomous mechanisms of aggregate formation have come to the fore, suggesting that nucleation-dependent aggregation may occur in a localized fashion in human tauopathies and synucleinopathies, followed by seed-dependent propagation. There is a long prodromal phase between the formation of protein aggregates and the appearance of the first clinical symptoms, which manifest only after extensive propagation, opening novel therapeutic avenues., (© The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
- Published
- 2017
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24. α-Synuclein: Experimental Pathology.
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Hasegawa M, Nonaka T, and Masuda-Suzukake M
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- Animals, Brain metabolism, Disease Models, Animal, Disease Progression, Humans, Lewy Body Disease pathology, Mice, Multiple System Atrophy pathology, Parkinson Disease pathology, Amyloid metabolism, Brain pathology, alpha-Synuclein metabolism
- Abstract
α-Synuclein, which is present as a small, soluble, cytosolic protein in healthy subjects, is converted to amyloid-like fibrils in diseases such as Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). Bulk synthesis of purified α-synuclein has made it more convenient to study the nature of the normal protein and the mechanism of its conversion to an abnormal form in vitro and in vivo. Synthetic α-synuclein fibrils and pathological α-synuclein from diseased brains can act as triggers to convert normal α-synuclein to an abnormal form via prion-like mechanisms. In this article, we describe the experimental pathologies of α-synuclein both in vitro and in vivo in human and animal models. Prion-like spreading of abnormal α-synuclein from cell to cell can account for the progression of these α-synucleinopathies., (Copyright © 2016 Cold Spring Harbor Laboratory Press; all rights reserved.)
- Published
- 2016
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25. Exposure to bacterial endotoxin generates a distinct strain of α-synuclein fibril.
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Kim C, Lv G, Lee JS, Jung BC, Masuda-Suzukake M, Hong CS, Valera E, Lee HJ, Paik SR, Hasegawa M, Masliah E, Eliezer D, and Lee SJ
- Subjects
- Animals, Cells, Cultured, Female, Humans, Mice, Mice, Inbred C57BL, Microglia cytology, Microglia metabolism, Neurons cytology, Neurons metabolism, Protein Structure, Tertiary, Protein Transport physiology, Amyloid metabolism, Lewy Body Disease pathology, Lipopolysaccharides metabolism, Multiple System Atrophy pathology, Parkinson Disease pathology, Protein Aggregates physiology, alpha-Synuclein metabolism
- Abstract
A single amyloidogenic protein is implicated in multiple neurological diseases and capable of generating a number of aggregate "strains" with distinct structures. Among the amyloidogenic proteins, α-synuclein generates multiple patterns of proteinopathies in a group of diseases, such as Parkinson disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). However, the link between specific conformations and distinct pathologies, the key concept of the strain hypothesis, remains elusive. Here we show that in the presence of bacterial endotoxin, lipopolysaccharide (LPS), α-synuclein generated a self-renewable, structurally distinct fibril strain that consistently induced specific patterns of synucleinopathies in mice. These results suggest that amyloid fibrils with self-renewable structures cause distinct types of proteinopathies despite the identical primary structure and that exposure to exogenous pathogens may contribute to the diversity of synucleinopathies.
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- 2016
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26. TDP-43 in the hypoglossal nucleus identifies amyotrophic lateral sclerosis in behavioral variant frontotemporal dementia.
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Halliday GM, Kiernan MC, Kril JJ, Mito R, Masuda-Suzukake M, Hasegawa M, McCann H, Bartley L, Dobson-Stone C, Kwok JBJ, Hornberger M, Hodges JR, and Tan RH
- Subjects
- Aged, Amyotrophic Lateral Sclerosis genetics, Amyotrophic Lateral Sclerosis metabolism, C9orf72 Protein, Cell Count, Cerebellum metabolism, Cerebellum pathology, Diagnosis, Differential, Female, Frontotemporal Dementia genetics, Frontotemporal Dementia metabolism, Humans, Hypoglossal Nerve metabolism, Hypoglossal Nerve pathology, Intercellular Signaling Peptides and Proteins genetics, Male, Medulla Oblongata metabolism, Middle Aged, Mutation, Neurons metabolism, Neurons pathology, Organ Size, Progranulins, Proteins genetics, Retrospective Studies, Severity of Illness Index, Spinal Cord metabolism, Spinal Cord pathology, Amyotrophic Lateral Sclerosis diagnosis, Amyotrophic Lateral Sclerosis pathology, DNA-Binding Proteins metabolism, Frontotemporal Dementia diagnosis, Frontotemporal Dementia pathology, Medulla Oblongata pathology
- Abstract
The hypoglossal nucleus was recently identified as a key brain region in which the presence of TDP-43 pathology could accurately discriminate TDP-43 proteinopathy cases with clinical amyotrophic lateral sclerosis (ALS). The objective of the present study was to assess the hypoglossal nucleus in behavioral variant frontotemporal dementia (bvFTD), and determine whether TDP-43 in this region is associated with clinical ALS. Twenty-nine cases with neuropathological FTLD-TDP and clinical bvFTD that had not been previously assessed for hypoglossal TDP-43 pathology were included in this study. Of these 29 cases, 41% (n=12) had a dual diagnosis of bvFTD-ALS at presentation, all 100% (n=12) of which demonstrated hypoglossal TDP-43 pathology. Of the 59% (n=17) cohort that presented with pure bvFTD, 35% (n=6) were identified with hypoglossal TDP-43 pathology. Review of the case files of all pure bvFTD cases revealed evidence of possible or probable ALS in 5 of the 6 hypoglossal-positive cases (83%) towards the end of disease, and this was absent from all cases without such pathology. In conclusion, the present study validates grading the presence of TDP-43 in the hypoglossal nucleus for the pathological identification of bvFTD cases with clinical ALS, and extends this to include the identification of cases with possible ALS at end-stage., (Crown Copyright © 2016. Published by Elsevier B.V. All rights reserved.)
- Published
- 2016
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27. Cerebellar neuronal loss in amyotrophic lateral sclerosis cases with ATXN2 intermediate repeat expansions.
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Tan RH, Kril JJ, McGinley C, Hassani M, Masuda-Suzukake M, Hasegawa M, Mito R, Kiernan MC, and Halliday GM
- Subjects
- Aged, C9orf72 Protein, DNA Repeat Expansion, Female, Humans, Male, Middle Aged, Proteins, Amyotrophic Lateral Sclerosis genetics, Amyotrophic Lateral Sclerosis pathology, Ataxin-2 genetics, Cerebellar Vermis pathology, Purkinje Cells pathology, Tissue Banks
- Abstract
Objective: Despite evidence suggesting that the cerebellum may be targeted in amyotrophic lateral sclerosis (ALS), particularly in cases with repeat expansions in the ATXN2 and C9ORF72 genes, the integrity of cerebellar neurons has yet to be examined. The present study undertakes a histopathological analysis to assess the impact of these repeat expansions on cerebellar neurons and determine whether similar cerebellar pathology occurs in sporadic disease., Methods: Purkinje and granule cells were quantified in the vermis and lateral cerebellar hemispheres of ALS cases with repeat expansions in the ATXN2 and C9ORF72 genes, sporadic disease, and sporadic progressive muscular atrophy with only lower motor neuron degeneration., Results: ALS cases with intermediate repeat expansions in the ATXN2 gene demonstrate a significant loss in Purkinje cells in the cerebellar vermis only. Despite ALS cases with expansions in the C9ORF72 gene having the highest burden of inclusion pathology, no neuronal loss was observed in this group. Neuronal numbers were also unchanged in sporadic ALS and sporadic PMA cases., Interpretation: The present study has established a selective loss of Purkinje cells in the cerebellar vermis of ALS cases with intermediate repeat expansions in the ATXN2 gene, suggesting a divergent pathogenic mechanism independent of upper and lower motor neuron degeneration in ALS. We discuss these findings in the context of large repeat expansions in ATXN2 and spinocerebellar ataxia type 2, providing evidence that intermediate repeats in ATXN2 cause significant, albeit less substantial, spinocerebellar damage compared with longer repeats in ATXN2., (© 2016 American Neurological Association.)
- Published
- 2016
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28. Biochemical classification of tauopathies by immunoblot, protein sequence and mass spectrometric analyses of sarkosyl-insoluble and trypsin-resistant tau.
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Taniguchi-Watanabe S, Arai T, Kametani F, Nonaka T, Masuda-Suzukake M, Tarutani A, Murayama S, Saito Y, Arima K, Yoshida M, Akiyama H, Robinson A, Mann DMA, Iwatsubo T, and Hasegawa M
- Subjects
- Aged, Aged, 80 and over, Amino Acid Sequence, Brain ultrastructure, Female, Humans, Male, Microscopy, Immunoelectron methods, Middle Aged, Protein Conformation, Sarcosine analogs & derivatives, Sarcosine metabolism, Tauopathies pathology, Trypsin metabolism, tau Proteins metabolism, Brain Chemistry, Immunoblotting methods, Mass Spectrometry methods, Sequence Analysis, Protein methods, Tauopathies classification, Tauopathies metabolism, tau Proteins chemistry
- Abstract
Intracellular filamentous tau pathology is the defining feature of tauopathies, which form a subset of neurodegenerative diseases. We have analyzed pathological tau in Alzheimer's disease, and in frontotemporal lobar degeneration associated with tauopathy to include cases with Pick bodies, corticobasal degeneration, progressive supranuclear palsy, and ones due to intronic mutations in MAPT. We found that the C-terminal band pattern of the pathological tau species is distinct for each disease. Immunoblot analysis of trypsin-resistant tau indicated that the different band patterns of the 7-18 kDa fragments in these diseases likely reflect different conformations of tau molecular species. Protein sequence and mass spectrometric analyses revealed the carboxyl-terminal region (residues 243-406) of tau comprises the protease-resistant core units of the tau aggregates, and the sequence lengths and precise regions involved are different among the diseases. These unique assembled tau cores may be used to classify and diagnose disease strains. Based on these results, we propose a new clinicopathological classification of tauopathies based on the biochemical properties of tau.
- Published
- 2016
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29. The Abundance of Nonphosphorylated Tau in Mouse and Human Tauopathy Brains Revealed by the Use of Phos-Tag Method.
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Kimura T, Hatsuta H, Masuda-Suzukake M, Hosokawa M, Ishiguro K, Akiyama H, Murayama S, Hasegawa M, and Hisanaga S
- Subjects
- Aged, Aged, 80 and over, Animals, Disease Models, Animal, Electrophoresis, Polyacrylamide Gel methods, Female, Humans, Male, Phosphorylation, Protein Isoforms metabolism, Alzheimer Disease metabolism, Brain metabolism, Neurons metabolism, tau Proteins metabolism
- Abstract
Tauopathies are neurodegenerative diseases characterized by aggregates of hyperphosphorylated tau. Previous studies have identified many disease-related phosphorylation sites on tau. However, it is not understood how tau is hyperphosphorylated and what extent these sites are phosphorylated in both diseased and normal brains. Most previous studies have used phospho-specific antibodies to analyze tau phosphorylation. These results are useful but do not provide information about nonphosphorylated tau. Here, we applied the method of Phos-tag SDS-PAGE, in which phosphorylated tau was separated from nonphosphorylated tau in vivo. Among heterogeneously phosphorylated tau species in adult mouse brains, the nonphosphorylated 0N4R isoform was detected most abundantly. In contrast, perinatal tau and tau in cold water-stressed mice were all phosphorylated with a similar extent of phosphorylation. In normal elderly human brains, nonphosphorylated 0N3R and 0N4R tau were most abundant. A slightly higher phosphorylation of tau, which may represent the early step of hyperphosphorylation, was increased in Alzheimer disease patients at Braak stage V. Tau with this phosphorylation state was pelleted by centrifugation, and sarkosyl-soluble tau in either Alzheimer disease or corticobasal degeneration brains showed phosphorylation profiles similar to tau in normal human brain, suggesting that hyperphosphorylation occurs in aggregated tau. These results indicate that tau molecules are present in multiple phosphorylation states in vivo, and nonphosphorylated forms are highly expressed among them., (Copyright © 2016 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2016
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30. Accumulation of dipeptide repeat proteins predates that of TDP-43 in frontotemporal lobar degeneration associated with hexanucleotide repeat expansions in C9ORF72 gene.
- Author
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Baborie A, Griffiths TD, Jaros E, Perry R, McKeith IG, Burn DJ, Masuda-Suzukake M, Hasegawa M, Rollinson S, Pickering-Brown S, Robinson AC, Davidson YS, and Mann DM
- Subjects
- Aged, Brain pathology, C9orf72 Protein, DNA Repeat Expansion, Female, Frontotemporal Lobar Degeneration genetics, Frontotemporal Lobar Degeneration pathology, Humans, Inclusion Bodies metabolism, Inclusion Bodies pathology, Male, Middle Aged, Neurons metabolism, Neurons pathology, Brain metabolism, DNA-Binding Proteins metabolism, Dipeptides metabolism, Frontotemporal Lobar Degeneration metabolism, Proteins genetics
- Abstract
Aims: Frontotemporal lobar degeneration (FTLD) and motor neurone disease are linked by the possession of a hexanucleotide repeat expansion in C9ORF72, and both show neuronal cytoplasmic inclusions within cerebellar and hippocampal neurones which are TDP-43 negative but immunoreactive for p62 and dipeptide repeat proteins (DPR), these being generated by a non-ATG RAN translation of the expanded region of the gene., Methods: Twenty-two cases of FTLD from Newcastle were analysed for an expansion in C9ORF72 by repeat primed PCR and Southern blot. Detailed case note analysis was performed, and blinded retrospective clinical impressions were achieved by review of clinical histories. Sections from all major brain regions were immunostained for TDP-43, p62 and DPR. The extent of TDP-43 and DPR pathology in expansion bearers was compared with that in 13 other previously identified cases from the Manchester Brain Bank with established disease., Results: Three Newcastle patients bearing an expansion in C9ORF72 were identified. These three patients died prematurely, two from bronchopneumonia within 10 months and 3 years of onset, and one from myocardial infarction 3 years after onset. In all three, DPR were plentiful throughout all cerebral cortical regions, hippocampus and cerebellum, but TDP-43 pathological changes were sparse. The severity of DPR pathological changes in these three patients was similar to that in the Manchester series, although the extent of TDP-43 pathology was significantly less., Conclusion: Widespread accumulation of DPR within nerve cells may occur much earlier than that of TDP-43 in patients with FTLD bearing expansion in C9ORF72., (© 2014 British Neuropathological Society.)
- Published
- 2015
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31. Progranulin reduction is associated with increased tau phosphorylation in P301L tau transgenic mice.
- Author
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Hosokawa M, Arai T, Masuda-Suzukake M, Kondo H, Matsuwaki T, Nishihara M, Hasegawa M, and Akiyama H
- Subjects
- Age Factors, Animals, Brain metabolism, Cyclin-Dependent Kinases metabolism, Intercellular Signaling Peptides and Proteins genetics, Isoleucine genetics, Mice, Mice, Inbred C57BL, Mice, Transgenic, Mitogen-Activated Protein Kinase Kinases metabolism, Phosphorylation genetics, Progranulins, Proline genetics, Gene Expression Regulation genetics, Intercellular Signaling Peptides and Proteins metabolism, Mutation genetics, tau Proteins genetics, tau Proteins metabolism
- Abstract
Granulin (GRN) mutations have been identified in familial frontotemporal lobar degeneration patients with ubiquitin pathology. GRN transcript haploinsufficiency is proposed as a disease mechanism that leads to the loss of functional progranulin (PGRN) protein. Thus, these mutations are strongly involved in frontotemporal lobar degeneration pathogenesis. Moreover, recent findings indicate that GRN mutations are associated with other neurodegenerative disorders with tau pathology, including Alzheimer disease and corticobasal degeneration. To investigate the potential influence of a decline in PGRN protein on tau accumulation, P301L tau transgenic mice were interbred with GRN-deficient mice, producing P301L tau transgenic mice harboring the GRN hemizygote. Brains were collected from 13- and 19-month-old mice, and sequential extraction of proteins, immunoblotting, and immunohistochemical analyses were performed. Immunoblotting analysis revealed that tau phosphorylation was accelerated in the Tris-saline soluble fraction of 13-month-old and in the sarkosyl-insoluble fraction of 19-month-old P301L tau/GRN hemizygotes compared with those in fractions from P301L tau transgenic mice. Activity of cyclin-dependent kinases was also upregulated in the brains of P301L tau/GRN hemizygote mice. Although the mechanisms involved in these findings remain unknown, our data suggest that a reduction in PGRN protein might contribute to phosphorylation and intraneuronal accumulation of tau.
- Published
- 2015
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32. C9ORF72 repeat-associated non-ATG-translated polypeptides are distributed independently of TDP-43 in a Japanese patient with c9ALS.
- Author
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Konno T, Tada M, Shiga A, Tsujino A, Eguchi H, Masuda-Suzukake M, Hasegawa M, Nishizawa M, Onodera O, Kakita A, and Takahashi H
- Subjects
- Amyotrophic Lateral Sclerosis genetics, Amyotrophic Lateral Sclerosis metabolism, Anterior Horn Cells metabolism, Asian People, Brain ultrastructure, C9orf72 Protein, Cerebellum metabolism, Cerebellum ultrastructure, Humans, Inclusion Bodies, Neurons metabolism, Neurons ultrastructure, Peptides analysis, Peptides genetics, Amyotrophic Lateral Sclerosis diagnosis, Brain metabolism, DNA Repeat Expansion, DNA-Binding Proteins analysis, Proteins analysis, Proteins genetics
- Published
- 2014
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33. Pathological alpha-synuclein propagates through neural networks.
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Masuda-Suzukake M, Nonaka T, Hosokawa M, Kubo M, Shimozawa A, Akiyama H, and Hasegawa M
- Subjects
- Animals, Brain drug effects, DNA-Binding Proteins metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, Nerve Net drug effects, Phosphorylation, Prions metabolism, Recombinant Proteins toxicity, alpha-Synuclein genetics, alpha-Synuclein toxicity, tau Proteins metabolism, Brain metabolism, Brain pathology, Nerve Net metabolism, Nerve Net pathology, alpha-Synuclein metabolism
- Abstract
Background: α-Synuclein is the major component of filamentous inclusions that constitute the defining characteristic of Parkinson's disease, dementia with Lewy bodies and multiple system atrophy, so-called α-synucleinopathies. Recent studies revealed that intracerebral injection of recombinant α-synuclein fibrils into wild-type mouse brains induced prion-like propagation of hyperphosphorylated α-synuclein pathology. However, the propagation mechanisms of α-synuclein have not been fully elucidated., Results: In this study, in order to establish where and how α-synuclein pathology propagates, we injected recombinant mouse α-synuclein fibrils into three different brain areas (substantia nigra, striatum, and entorhinal cortex) of wild-type mice and compared the resulting distributions of α-synuclein pathology at 1 month after injection. Distinct patterns of pathology were observed in mice injected at the different sites. Within one month after injection, the pathology had spread to neurons in areas far from the injection sites, especially areas with direct neural connections to the injection sites. Surprisingly, phosphorylated tau and TDP-43 pathologies were also observed in mice injected with α-synuclein fibrils into striatum and entorhinal cortex at one month after injection. Phosphorylated tau and TDP-43 were accumulated in dot-like inclusions, but these were rarely colocalized with α-synuclein pathology. It seems that accumulation of α-synuclein has a synergistic effect on tau and TDP-43 aggregation. Additionally, intracerebral injection with sarkosyl-insoluble fraction prepared from wild-type mice injected synthetic α-synuclein fibrils can also induce phosphorylated α-synuclein pathology in wild-type mice., Conclusions: Our data indicate that α-synuclein aggregation spread by prion-like mechanisms through neural networks in mouse brains.
- Published
- 2014
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34. Brain distribution of dipeptide repeat proteins in frontotemporal lobar degeneration and motor neurone disease associated with expansions in C9ORF72.
- Author
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Davidson YS, Barker H, Robinson AC, Thompson JC, Harris J, Troakes C, Smith B, Al-Saraj S, Shaw C, Rollinson S, Masuda-Suzukake M, Hasegawa M, Pickering-Brown S, Snowden JS, and Mann DM
- Subjects
- Adult, Aged, Apolipoproteins E, C9orf72 Protein, DNA Mutational Analysis, DNA-Binding Proteins, Female, Gene Expression Regulation genetics, Humans, Male, Middle Aged, Brain metabolism, DNA Repeat Expansion genetics, Dipeptides metabolism, Frontotemporal Lobar Degeneration genetics, Frontotemporal Lobar Degeneration pathology, Motor Neuron Disease genetics, Motor Neuron Disease pathology, Proteins genetics
- Abstract
A hexanucleotide (GGGGCC) expansion in C9ORF72 gene is the most common genetic change seen in familial Frontotemporal Lobar Degeneration (FTLD) and familial Motor Neurone Disease (MND). Pathologically, expansion bearers show characteristic p62 positive, TDP-43 negative inclusion bodies within cerebellar and hippocampal neurons which also contain dipeptide repeat proteins (DPR) formed from sense and antisense RAN (repeat associated non ATG-initiated) translation of the expanded repeat region itself. 'Inappropriate' formation, and aggregation, of DPR might therefore confer neurotoxicity and influence clinical phenotype. Consequently, we compared the topographic brain distribution of DPR in 8 patients with Frontotemporal dementia (FTD), 6 with FTD + MND and 7 with MND alone (all 21 patients bearing expansions in C9ORF72) using a polyclonal antibody to poly-GA, and related this to the extent of TDP-43 pathology in key regions of cerebral cortex and hippocampus. There were no significant differences in either the pattern or severity of brain distribution of DPR between FTD, FTD + MND and MND groups, nor was there any relationship between the distribution of DPR and TDP-43 pathologies in expansion bearers. Likewise, there were no significant differences in the extent of TDP-43 pathology between FTLD patients bearing an expansion in C9ORF72 and non-bearers of the expansion. There were no association between the extent of DPR pathology and TMEM106B or APOE genotypes. However, there was a negative correlation between the extent of DPR pathology and age at onset. Present findings therefore suggest that although the presence and topographic distribution of DPR may be of diagnostic relevance in patients bearing expansion in C9ORF72 this has no bearing on the determination of clinical phenotype. Because TDP-43 pathologies are similar in bearers and non-bearers of the expansion, the expansion may act as a major genetic risk factor for FTLD and MND by rendering the brain highly vulnerable to those very same factors which generate FTLD and MND in sporadic disease.
- Published
- 2014
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35. Differential diagnosis of amyotrophic lateral sclerosis from Guillain-Barré syndrome by quantitative determination of TDP-43 in cerebrospinal fluid.
- Author
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Hosokawa M, Arai T, Yamashita M, Tsuji H, Nonaka T, Masuda-Suzukake M, Tamaoka A, Hasegawa M, and Akiyama H
- Subjects
- Adult, Aged, Amyotrophic Lateral Sclerosis cerebrospinal fluid, Biomarkers cerebrospinal fluid, Cell Line, Tumor, Diagnosis, Differential, Enzyme-Linked Immunosorbent Assay, Female, Guillain-Barre Syndrome cerebrospinal fluid, Humans, Immunoprecipitation methods, Male, Middle Aged, Young Adult, Amyotrophic Lateral Sclerosis diagnosis, DNA-Binding Proteins cerebrospinal fluid, Guillain-Barre Syndrome diagnosis, TDP-43 Proteinopathies cerebrospinal fluid
- Abstract
The aim of this study was to investigate whether an increased level of TAR DNA-binding protein 43 (TDP-43) in the cerebrospinal fluid (CSF) could be a biomarker for amyotrophic lateral sclerosis (ALS) and facilitate differential diagnosis of ALS from peripheral motor neuropathy. TDP-43 is the major constituent of neuronal and glial inclusions that neuropathologically characterize both ALS and tau-negative frontotemporal lobar degeneration. Recent discoveries of various missense mutations in the TDP-43 gene in familial ALS indicate a pivotal role of the aberrant accumulation of TDP-43 in neurodegeneration. Increased TDP-43 in the CSF could be a hallmark of ALS and other TDP-43 proteinopathy. Sandwich enzyme-linked immunosorbent assay (ELISA) was established to measure the concentration of TDP-43 in biological fluids. Culture supernatants of cells transfected with various TDP-43 constructs were used to confirm that the ELISA detected TDP-43. TDP-43 in the culture supernatant of TDP-43 transfected cells was detected by immunoprecipitation with subsequent immunoblotting and concentrations were successfully measured by sandwich ELISA. We then measured TDP-43 concentrations in the CSF of patients with ALS and Guillain-Barré syndrome (GBS). TDP-43 concentrations in CSF were significantly higher in ALS than in GBS (p = 0.016). The sensitivity of the diagnostic test was 71.4% and the specificity was 84.6%. Quantitative determination of TDP-43 concentrations in the CSF by sandwich ELISA is a potential laboratory test for differentiating ALS from peripheral motor neuropathies such as GBS.
- Published
- 2014
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36. Dipeptide repeat proteins are present in the p62 positive inclusions in patients with frontotemporal lobar degeneration and motor neurone disease associated with expansions in C9ORF72.
- Author
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Mann DM, Rollinson S, Robinson A, Bennion Callister J, Thompson JC, Snowden JS, Gendron T, Petrucelli L, Masuda-Suzukake M, Hasegawa M, Davidson Y, and Pickering-Brown S
- Subjects
- Aged, Blotting, Southern, Brain physiology, C9orf72 Protein, Cytoplasm metabolism, Cytoplasm pathology, DNA Repeat Expansion, Female, Frontotemporal Lobar Degeneration genetics, Frontotemporal Lobar Degeneration pathology, Humans, Inclusion Bodies pathology, Male, Middle Aged, Motor Neuron Disease genetics, Motor Neuron Disease pathology, Neurons metabolism, Neurons pathology, Brain metabolism, Frontotemporal Lobar Degeneration metabolism, Inclusion Bodies metabolism, Motor Neuron Disease metabolism, Proteins genetics, RNA-Binding Proteins metabolism
- Abstract
Background: Cases of Frontotemporal Lobar Degeneration (FTLD) and Motor Neurone Disease (MND) associated with expansions in C9ORF72 gene are characterised pathologically by the presence of TDP-43 negative, but p62 positive, inclusions in granule cells of the cerebellum and in cells of dentate gyrus and area CA4 of the hippocampus., Results: We screened 84 cases of pathologically confirmed FTLD and 23 cases of MND for the presence of p62 positive inclusions in these three brain regions, and identified 13 positive cases of FTLD and 3 of MND. All cases demonstrated expansions in C9ORF72 by Southern blotting where frozen tissues were available. The p62 positive inclusions in both cerebellum and hippocampus were immunostained by antibodies to dipeptide repeat proteins (DPR), poly Gly-Ala (poly-GA), poly Gly-Pro (poly-GP) and poly Gly-Arg (poly-GR), these arising from a putative non-ATG initiated (RAN) sense translation of the GGGGCC expansion. There was also some slight, but variable, immunostaining with poly-AP antibody implying some antisense translation might also occur, though the relative paucity of immunostaining could reflect poor antigen avidity on the part of the antisense antibodies. Of the FTLD cases with DPR, 6 showed TDP-43 type A and 6 had TDP-43 type B histology; one had FTLD-tau with the pathology of corticobasal degeneration. There were no qualitative or quantitative differences in the pattern of immunostaining with antibodies to DPR, or p62, proteins between TDP-43 type A and type B cases. Ratings for frequency of inclusions immunostained by these poly-GA, poly-GP and poly-GR antibodies broadly correlated with those for immunolabelled by p62 antibody in all three regions., Conclusion: We conclude that DPR are a major component of p62 positive inclusions in FTLD and MND.
- Published
- 2013
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37. Extensive deamidation at asparagine residue 279 accounts for weak immunoreactivity of tau with RD4 antibody in Alzheimer's disease brain.
- Author
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Dan A, Takahashi M, Masuda-Suzukake M, Kametani F, Nonaka T, Kondo H, Akiyama H, Arai T, Mann DM, Saito Y, Hatsuta H, Murayama S, and Hasegawa M
- Subjects
- Antibodies genetics, Asparagine, Humans, Immunoblotting, Immunohistochemistry, Microtubules metabolism, Mutation, Protein Isoforms genetics, Protein Isoforms immunology, Protein Processing, Post-Translational, Recombinant Proteins metabolism, Supranuclear Palsy, Progressive metabolism, tau Proteins chemistry, tau Proteins genetics, Alzheimer Disease metabolism, Antibodies immunology, Brain metabolism, tau Proteins immunology, tau Proteins metabolism
- Abstract
Background: Intracytoplasmic inclusions composed of filamentous tau proteins are defining characteristics of neurodegenerative tauopathies, but it remains unclear why different tau isoforms accumulate in different diseases and how they induce abnormal filamentous structures and pathologies. Two tau isoform-specific antibodies, RD3 and RD4, are widely used for immunohistochemical and biochemical studies of tau species in diseased brains., Results: Here, we show that extensive irreversible post-translational deamidation takes place at asparagine residue 279 (N279) in the RD4 epitope of tau in Alzheimer's disease (AD), but not corticobasal degeneration (CBD) or progressive supranuclear palsy (PSP), and this modification abrogates the immunoreactivity to RD4. An antiserum raised against deamidated RD4 peptide specifically recognized 4R tau isoforms, regardless of deamidation, and strongly stained tau in AD brain. We also found that mutant tau with N279D substitution showed reduced ability to bind to microtubules and to promote microtubule assembly., Conclusion: The biochemical and structural differences of tau in AD from that in 4R tauopathies found in this study may therefore have implications for prion-like propagation of tau.
- Published
- 2013
- Full Text
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38. Prion-like properties of pathological TDP-43 aggregates from diseased brains.
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Nonaka T, Masuda-Suzukake M, Arai T, Hasegawa Y, Akatsu H, Obi T, Yoshida M, Murayama S, Mann DM, Akiyama H, and Hasegawa M
- Subjects
- Apoptosis, Cell Line, Tumor, Exosomes metabolism, HEK293 Cells, Humans, Phosphorylation, Protein Denaturation, Proteolysis, Ubiquitination, Amyotrophic Lateral Sclerosis metabolism, Brain metabolism, Frontotemporal Dementia metabolism, Inclusion Bodies metabolism, Polymerization, Proteasome Endopeptidase Complex metabolism
- Abstract
TDP-43 is the major component protein of ubiquitin-positive inclusions in brains of patients with frontotemporal lobar degeneration (FTLD-TDP) or amyotrophic lateral sclerosis (ALS). Here, we report the characterization of prion-like properties of aggregated TDP-43 prepared from diseased brains. When insoluble TDP-43 from ALS or FTLD-TDP brains was introduced as seeds into SH-SY5Y cells expressing TDP-43, phosphorylated and ubiquitinated TDP-43 was aggregated in a self-templating manner. Immunoblot analyses revealed that the C-terminal fragments of insoluble TDP-43 characteristic of each disease type acted as seeds, inducing seed-dependent aggregation of TDP-43 in these cells. The seeding ability of insoluble TDP-43 was unaffected by proteinase treatment but was abrogated by formic acid. One subtype of TDP-43 aggregate was resistant to boiling treatment. The insoluble fraction from cells harboring TDP-43 aggregates could also trigger intracellular TDP-43 aggregation. These results indicate that insoluble TDP-43 has prion-like properties that may play a role in the progression of TDP-43 proteinopathy., (Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2013
- Full Text
- View/download PDF
39. Prion-like spreading of pathological α-synuclein in brain.
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Masuda-Suzukake M, Nonaka T, Hosokawa M, Oikawa T, Arai T, Akiyama H, Mann DM, and Hasegawa M
- Subjects
- Administration, Intranasal, Animals, Behavior, Animal physiology, Brain physiopathology, Disease Models, Animal, Female, Humans, Injections, Intraventricular, Lewy Body Disease metabolism, Lewy Body Disease pathology, Lewy Body Disease physiopathology, Mice, Mice, Inbred C57BL, Recombinant Proteins administration & dosage, Recombinant Proteins toxicity, Time Factors, alpha-Synuclein administration & dosage, alpha-Synuclein toxicity, Brain metabolism, Brain pathology, Prions metabolism, alpha-Synuclein metabolism
- Abstract
α-Synuclein is the major component of filamentous inclusions that constitute the defining characteristic of neurodegenerative α-synucleinopathies. However, the molecular mechanisms underlying α-synuclein accumulation and spread are unclear. Here we show that intracerebral injections of sarkosyl-insoluble α-synuclein from brains of patients with dementia with Lewy bodies induced hyperphosphorylated α-synuclein pathology in wild-type mice. Furthermore, injection of fibrils of recombinant human and mouse α-synuclein efficiently induced similar α-synuclein pathologies in wild-type mice. C57BL/6J mice injected with α-synuclein fibrils developed abundant Lewy body/Lewy neurite-like pathology, whereas mice injected with soluble α-synuclein did not. Immunoblot analysis demonstrated that endogenous mouse α-synuclein started to accumulate 3 months after inoculation, while injected human α-synuclein fibrils disappeared in about a week. These results indicate that α-synuclein fibrils have prion-like properties and inoculation into wild-type brain induces α-synuclein pathology in vivo. This is a new mouse model of sporadic α-synucleinopathy and should be useful for elucidating progression mechanisms and evaluating disease-modifying therapy.
- Published
- 2013
- Full Text
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40. Isomerase Pin1 stimulates dephosphorylation of tau protein at cyclin-dependent kinase (Cdk5)-dependent Alzheimer phosphorylation sites.
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Kimura T, Tsutsumi K, Taoka M, Saito T, Masuda-Suzukake M, Ishiguro K, Plattner F, Uchida T, Isobe T, Hasegawa M, and Hisanaga SI
- Subjects
- Animals, Base Sequence, Brain metabolism, COS Cells, Chlorocebus aethiops, Humans, Kinetics, Mice, Molecular Sequence Data, NIMA-Interacting Peptidylprolyl Isomerase, Phosphorylation, Plasmids metabolism, Protein Binding, Protein Isoforms, Tauopathies metabolism, Alzheimer Disease metabolism, Cyclin-Dependent Kinase 5 physiology, Mutation, Peptidylprolyl Isomerase metabolism, tau Proteins metabolism
- Abstract
Neurodegenerative diseases associated with the pathological aggregation of microtubule-associated protein Tau are classified as tauopathies. Alzheimer disease, the most common tauopathy, is characterized by neurofibrillary tangles that are mainly composed of abnormally phosphorylated Tau. Similar hyperphosphorylated Tau lesions are found in patients with frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) that is induced by mutations within the tau gene. To further understand the etiology of tauopathies, it will be important to elucidate the mechanism underlying Tau hyperphosphorylation. Tau phosphorylation occurs mainly at proline-directed Ser/Thr sites, which are targeted by protein kinases such as GSK3β and Cdk5. We reported previously that dephosphorylation of Tau at Cdk5-mediated sites was enhanced by Pin1, a peptidyl-prolyl isomerase that stimulates dephosphorylation at proline-directed sites by protein phosphatase 2A. Pin1 deficiency is suggested to cause Tau hyperphosphorylation in Alzheimer disease. Up to the present, Pin1 binding was only shown for two Tau phosphorylation sites (Thr-212 and Thr-231) despite the presence of many more hyperphosphorylated sites. Here, we analyzed the interaction of Pin1 with Tau phosphorylated by Cdk5-p25 using a GST pulldown assay and Biacore approach. We found that Pin1 binds and stimulates dephosphorylation of Tau at all Cdk5-mediated sites (Ser-202, Thr-205, Ser-235, and Ser-404). Furthermore, FTDP-17 mutant Tau (P301L or R406W) showed slightly weaker Pin1 binding than non-mutated Tau, suggesting that FTDP-17 mutations induce hyperphosphorylation by reducing the interaction between Pin1 and Tau. Together, these results indicate that Pin1 is generally involved in the regulation of Tau hyperphosphorylation and hence the etiology of tauopathies.
- Published
- 2013
- Full Text
- View/download PDF
41. A longitudinal study on α-synuclein in blood plasma as a biomarker for Parkinson's disease.
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Foulds PG, Diggle P, Mitchell JD, Parker A, Hasegawa M, Masuda-Suzukake M, Mann DM, and Allsop D
- Subjects
- Adult, Age Factors, Aged, Aged, 80 and over, Biomarkers blood, Case-Control Studies, Female, Humans, Longitudinal Studies, Male, Middle Aged, Parkinson Disease diagnosis, Phosphorylation, ROC Curve, Reproducibility of Results, Sex Factors, Parkinson Disease blood, alpha-Synuclein blood
- Abstract
There have been no longitudinal studies on α-synuclein as a potential biomarker for the progression of Parkinson's disease (PD). Here, blood plasma 'total α-synuclein' and 'Ser-129 phosphorylated α-synuclein' were assayed at 4-6 monthly intervals from a cohort of 189 newly-diagnosed patients with PD. For log-transformed data, plasma total α-synuclein levels increased with time for up to 20 yrs after the appearance of initial symptoms (p = 0.012), whereas phosphorylated α-synuclein remained constant over this same period. The mean level of phosphorylated α-synuclein, but not of total α-synuclein, was higher in the PD plasma samples taken at first visit than in single samples taken from a group of 91 healthy controls (p = 0.012). Overall, we conclude that the plasma level of phosphorylated α-synuclein has potential value as a diagnostic tool, whereas the level of total α-synuclein could act as a surrogate marker for the progression of PD.
- Published
- 2013
- Full Text
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42. Epitope mapping of antibodies against TDP-43 and detection of protease-resistant fragments of pathological TDP-43 in amyotrophic lateral sclerosis and frontotemporal lobar degeneration.
- Author
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Tsuji H, Nonaka T, Yamashita M, Masuda-Suzukake M, Kametani F, Akiyama H, Mann DM, Tamaoka A, and Hasegawa M
- Subjects
- Amino Acid Sequence, Animals, Antibodies chemistry, Antibodies, Monoclonal chemistry, Antibodies, Monoclonal immunology, Brain immunology, Brain metabolism, Brain Chemistry, DNA-Binding Proteins chemistry, DNA-Binding Proteins metabolism, Humans, Mice, Molecular Sequence Data, Peptide Hydrolases chemistry, Amyotrophic Lateral Sclerosis metabolism, Antibodies immunology, DNA-Binding Proteins immunology, Epitope Mapping, Frontotemporal Lobar Degeneration metabolism
- Abstract
TAR DNA-binding protein of 43 kDa (TDP-43) is the major component of the intracellular inclusions in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Here, we show that both monoclonal (60019-2-Ig) and polyclonal (10782-2-AP) anti-TDP-43 antibodies recognize amino acids 203-209 of human TDP-43. The monoclonal antibody labeled human TDP-43 by recognizing Glu204, Asp205 and Arg208, but failed to react with mouse TDP-43. The antibodies stained the abnormally phosphorylated C-terminal fragments of 24-26 kDa in addition to normal TDP-43 in ALS and FTLD brains. Immunoblot analysis after protease treatment demonstrated that the epitope of the antibodies (residues 203-209) constitutes part of the protease-resistant domain of TDP-43 aggregates which determine a common characteristic of the pathological TDP-43 in both ALS and FTLD-TDP. The antibodies and methods used in this study will be useful for the characterization of abnormal TDP-43 in human materials, as well as in vitro and animal models for TDP-43 proteinopathies., (Copyright © 2011 Elsevier Inc. All rights reserved.)
- Published
- 2012
- Full Text
- View/download PDF
43. Methylene blue reduced abnormal tau accumulation in P301L tau transgenic mice.
- Author
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Hosokawa M, Arai T, Masuda-Suzukake M, Nonaka T, Yamashita M, Akiyama H, and Hasegawa M
- Subjects
- Animals, Brain metabolism, Brain pathology, Immunoblotting, Immunohistochemistry, Mice, Mice, Transgenic, Mutant Proteins chemistry, Mutant Proteins genetics, Phosphorylation drug effects, Protein Structure, Quaternary, Sarcosine analogs & derivatives, Sarcosine pharmacology, Solubility, Subcellular Fractions metabolism, tau Proteins chemistry, Amino Acid Substitution, Methylene Blue pharmacology, Mutant Proteins metabolism, tau Proteins genetics, tau Proteins metabolism
- Abstract
In neurodegenerative disorders, abnormally hyperphosphorylated and aggregated tau accumulates intracellularly, a mechanism which is thought to induce neuronal cell death. Methylene blue, a type of phenothiazine, has been reported to inhibit tau aggregation in vitro. However, the effect of methylene blue in vivo has remained unknown. Therefore, we examined whether methylene blue suppresses abnormal tau accumulation using P301L tau transgenic mice. At 8 to 11 months of age, these mice were orally administered methylene blue for 5 months. Subsequent results of Western blotting analysis revealed that this agent reduced detergent-insoluble phospho-tau. Methylene blue may have potential as a drug candidate for the treatment of tauopathy.
- Published
- 2012
- Full Text
- View/download PDF
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