20 results on '"Miller CCJ"'
Search Results
2. Stimulating VAPB-PTPIP51 ER-mitochondria tethering corrects FTD/ALS mutant TDP43 linked Ca 2+ and synaptic defects.
- Author
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Markovinovic A, Martín-Guerrero SM, Mórotz GM, Salam S, Gomez-Suaga P, Paillusson S, Greig J, Lee Y, Mitchell JC, Noble W, and Miller CCJ
- Subjects
- Humans, Calcium metabolism, Endoplasmic Reticulum metabolism, Glycogen Synthase Kinase 3 beta metabolism, Mitochondria metabolism, Protein Tyrosine Phosphatases metabolism, Synapses pathology, TDP-43 Proteinopathies metabolism, Amyotrophic Lateral Sclerosis pathology, Frontotemporal Dementia genetics, Frontotemporal Dementia metabolism, Neurodegenerative Diseases metabolism, Vesicular Transport Proteins genetics
- Abstract
Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are clinically linked major neurodegenerative diseases. Notably, TAR DNA-binding protein-43 (TDP43) accumulations are hallmark pathologies of FTD/ALS and mutations in the gene encoding TDP43 cause familial FTD/ALS. There are no cures for FTD/ALS. FTD/ALS display damage to a broad range of physiological functions, many of which are regulated by signaling between the endoplasmic reticulum (ER) and mitochondria. This signaling is mediated by the VAPB-PTPIP51 tethering proteins that serve to recruit regions of ER to the mitochondrial surface so as to facilitate inter-organelle communications. Several studies have now shown that disrupted ER-mitochondria signaling including breaking of the VAPB-PTPIP51 tethers are features of FTD/ALS and that for TDP43 and other familial genetic FTD/ALS insults, this involves activation of glycogen kinase-3β (GSK3β). Such findings have prompted suggestions that correcting damage to ER-mitochondria signaling and the VAPB-PTPIP51 interaction may be broadly therapeutic. Here we provide evidence to support this notion. We show that overexpression of VAPB or PTPIP51 to enhance ER-mitochondria signaling corrects mutant TDP43 induced damage to inositol 1,4,5-trisphosphate (IP3) receptor delivery of Ca
2+ to mitochondria which is a primary function of the VAPB-PTPIP51 tethers, and to synaptic function. Moreover, we show that ursodeoxycholic acid (UDCA), an FDA approved drug linked to FTD/ALS and other neurodegenerative diseases therapy and whose precise therapeutic target is unclear, corrects TDP43 linked damage to the VAPB-PTPIP51 interaction. We also show that this effect involves inhibition of TDP43 mediated activation of GSK3β. Thus, correcting damage to the VAPB-PTPIP51 tethers may have therapeutic value for FTD/ALS and other age-related neurodegenerative diseases., (© 2024. The Author(s).)- Published
- 2024
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3. A revised nomenclature for the lemur family of protein kinases.
- Author
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Mórotz GM, Bradbury NA, Caluseriu O, Hisanaga SI, Miller CCJ, Swiatecka-Urban A, Lenz HJ, Moss SJ, and Giamas G
- Subjects
- Animals, Protein Kinases, Phosphorylation, Axonal Transport, Lemur, Cystic Fibrosis
- Abstract
The lemur family of protein kinases has gained much interest in recent years as they are involved in a variety of cellular processes including regulation of axonal transport and endosomal trafficking, modulation of synaptic functions, memory and learning, and they are centrally placed in several intracellular signalling pathways. Numerous studies have also implicated role of the lemur kinases in the development and progression of a wide range of cancers, cystic fibrosis, and neurodegenerative diseases. However, parallel discoveries and inaccurate prediction of their kinase activity have resulted in a confusing and misleading nomenclature of these proteins. Herein, a group of international scientists with expertise in lemur family of protein kinases set forth a novel nomenclature to rectify this problem and ultimately help the scientific community by providing consistent information about these molecules., (© 2024. The Author(s).)
- Published
- 2024
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4. Poor communication between ER and mitochondria: a signature of ALS/FTD?
- Author
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Miller CCJ and Gomez-Suaga P
- Subjects
- Humans, DNA Repeat Expansion, Mitochondria, Amyotrophic Lateral Sclerosis genetics, Frontotemporal Dementia genetics
- Published
- 2023
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5. The PTPIP51 coiled-coil domain is important in VAPB binding, formation of ER-mitochondria contacts and IP3 receptor delivery of Ca 2+ to mitochondria.
- Author
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Mórotz GM, Martín-Guerrero SM, Markovinovic A, Paillusson S, Russell MRG, Machado PMP, Fleck RA, Noble W, and Miller CCJ
- Abstract
Signaling between the endoplasmic reticulum (ER) and mitochondria regulates a number of fundamental physiological processes. This signaling involves close physical contacts between the two organelles that are mediated by the VAPB-PTPIP51 ″tethering" proteins. The VAPB-PTPIP51 tethers facilitate inositol 1,4,5-trisphosphate (IP3) receptor delivery of Ca
2+ from ER to mitochondria. Damage to the tethers is seen in Alzheimer's disease, Parkinson's disease and frontotemporal dementia with related amyotrophic lateral sclerosis (FTD/ALS). Understanding the mechanisms that regulate the VAPB-PTPIP51 interaction thus represents an important area of research. Recent studies suggest that an FFAT motif in PTPIP51 is key to its binding to VAPB but this work relies on in vitro studies with short peptides. Cellular studies to support this notion with full-length proteins are lacking. Here we address this issue. Immunoprecipitation assays from transfected cells revealed that deletion of the PTPIP51 FFAT motif has little effect on VAPB binding. However, mutation and deletion of a nearby coiled-coil domain markedly affect this binding. Using electron microscopy, we then show that deletion of the coiled-coil domain but not the FFAT motif abrogates the effect of PTPIP51 on ER-mitochondria contacts. Finally, we show that deletion of the coiled-coil domain but not the FFAT motif abrogates the effect of PTPIP51 on the IP3 receptor-mediated delivery of Ca2+ to mitochondria. Thus, the coiled-coil domain is essential for PTPIP51 ER-mitochondria signaling functions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Mórotz, Martín-Guerrero, Markovinovic, Paillusson, Russell, Machado, Fleck, Noble and Miller.)- Published
- 2022
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6. Disruption of the VAPB-PTPIP51 ER-mitochondria tethering proteins in post-mortem human amyotrophic lateral sclerosis.
- Author
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Hartopp N, Lau DHW, Martin-Guerrero SM, Markovinovic A, Mórotz GM, Greig J, Glennon EB, Troakes C, Gomez-Suaga P, Noble W, and Miller CCJ
- Abstract
Signaling between the endoplasmic reticulum (ER) and mitochondria regulates many neuronal functions that are perturbed in amyotrophic lateral sclerosis (ALS) and perturbation to ER-mitochondria signaling is seen in cell and transgenic models of ALS. However, there is currently little evidence that ER-mitochondria signaling is altered in human ALS. ER-mitochondria signaling is mediated by interactions between the integral ER protein VAPB and the outer mitochondrial membrane protein PTPIP51 which act to recruit and "tether" regions of ER to the mitochondrial surface. The VAPB-PTPI51 tethers are now known to regulate a number of ER-mitochondria signaling functions. These include delivery of Ca
2+ from ER stores to mitochondria, mitochondrial ATP production, autophagy and synaptic activity. Here we investigate the VAPB-PTPIP51 tethers in post-mortem control and ALS spinal cords. We show that VAPB protein levels are reduced in ALS. Proximity ligation assays were then used to quantify the VAPB-PTPIP51 interaction in spinal cord motor neurons in control and ALS cases. These studies revealed that the VAPB-PTPIP51 tethers are disrupted in ALS. Thus, we identify a new pathogenic event in post-mortem ALS., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Hartopp, Lau, Martin-Guerrero, Markovinovic, Mórotz, Greig, Glennon, Troakes, Gomez-Suaga, Noble and Miller.)- Published
- 2022
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7. Targeting ER-Mitochondria Signaling as a Therapeutic Target for Frontotemporal Dementia and Related Amyotrophic Lateral Sclerosis.
- Author
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Martín-Guerrero SM, Markovinovic A, Mórotz GM, Salam S, Noble W, and Miller CCJ
- Abstract
Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are two major neurodegenerative diseases. FTD is the second most common cause of dementia and ALS is the most common form of motor neuron disease. These diseases are now known to be linked. There are no cures or effective treatments for FTD or ALS and so new targets for therapeutic intervention are required but this is hampered by the large number of physiological processes that are damaged in FTD/ALS. Many of these damaged functions are now known to be regulated by signaling between the endoplasmic reticulum (ER) and mitochondria. This signaling is mediated by "tethering" proteins that serve to recruit ER to mitochondria. One tether strongly associated with FTD/ALS involves an interaction between the ER protein VAPB and the mitochondrial protein PTPIP51. Recent studies have shown that ER-mitochondria signaling is damaged in FTD/ALS and that this involves breaking of the VAPB-PTPIP51 tethers. Correcting disrupted tethering may therefore correct many other downstream damaged features of FTD/ALS. Here, we review progress on this topic with particular emphasis on targeting of the VAPB-PTPIP51 tethers as a new drug target., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Martín-Guerrero, Markovinovic, Mórotz, Salam, Noble and Miller.)
- Published
- 2022
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8. Disruption of ER-mitochondria tethering and signalling in C9orf72-associated amyotrophic lateral sclerosis and frontotemporal dementia.
- Author
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Gomez-Suaga P, Mórotz GM, Markovinovic A, Martín-Guerrero SM, Preza E, Arias N, Mayl K, Aabdien A, Gesheva V, Nishimura A, Annibali A, Lee Y, Mitchell JC, Wray S, Shaw C, Noble W, and Miller CCJ
- Subjects
- Animals, C9orf72 Protein genetics, C9orf72 Protein metabolism, Calcium metabolism, Endoplasmic Reticulum metabolism, Humans, Mice, Mitochondria metabolism, Mitochondrial Proteins metabolism, Protein Tyrosine Phosphatases metabolism, Amyotrophic Lateral Sclerosis pathology, Frontotemporal Dementia genetics, Frontotemporal Dementia metabolism, Frontotemporal Dementia pathology
- Abstract
Hexanucleotide repeat expansions in C9orf72 are the most common cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The mechanisms by which the expansions cause disease are not properly understood but a favoured route involves its translation into dipeptide repeat (DPR) polypeptides, some of which are neurotoxic. However, the precise targets for mutant C9orf72 and DPR toxicity are not fully clear, and damage to several neuronal functions has been described. Many of these functions are regulated by signalling between the endoplasmic reticulum (ER) and mitochondria. ER-mitochondria signalling requires close physical contacts between the two organelles that are mediated by the VAPB-PTPIP51 'tethering' proteins. Here, we show that ER-mitochondria signalling and the VAPB-PTPIP51 tethers are disrupted in neurons derived from induced pluripotent stem (iPS) cells from patients carrying ALS/FTD pathogenic C9orf72 expansions and in affected neurons in mutant C9orf72 transgenic mice. In these mice, disruption of the VAPB-PTPIP51 tethers occurs prior to disease onset suggesting that it contributes to the pathogenic process. We also show that neurotoxic DPRs disrupt the VAPB-PTPIP51 interaction and ER-mitochondria contacts and that this may involve activation of glycogen synthase kinases-3β (GSK3β), a known negative regulator of VAPB-PTPIP51 binding. Finally, we show that these DPRs disrupt delivery of Ca
2+ from ER stores to mitochondria, which is a primary function of the VAPB-PTPIP51 tethers. This delivery regulates a number of key neuronal functions that are damaged in ALS/FTD including bioenergetics, autophagy and synaptic function. Our findings reveal a new molecular target for mutant C9orf72-mediated toxicity., (© 2022 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)- Published
- 2022
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9. Disruption of endoplasmic reticulum-mitochondria tethering proteins in post-mortem Alzheimer's disease brain.
- Author
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Lau DHW, Paillusson S, Hartopp N, Rupawala H, Mórotz GM, Gomez-Suaga P, Greig J, Troakes C, Noble W, and Miller CCJ
- Subjects
- Aged, Aged, 80 and over, Alzheimer Disease pathology, Autopsy, Endoplasmic Reticulum pathology, Female, Humans, Male, Mitochondria pathology, Pyramidal Cells metabolism, Pyramidal Cells pathology, Temporal Lobe pathology, Alzheimer Disease metabolism, Endoplasmic Reticulum metabolism, Mitochondria metabolism, Mitochondrial Proteins metabolism, Protein Tyrosine Phosphatases metabolism, Temporal Lobe metabolism, Vesicular Transport Proteins metabolism
- Abstract
Signaling between the endoplasmic reticulum (ER) and mitochondria regulates a number of key neuronal functions, many of which are perturbed in Alzheimer's disease. Moreover, damage to ER-mitochondria signaling is seen in cell and transgenic models of Alzheimer's disease. However, as yet there is little evidence that ER-mitochondria signaling is altered in human Alzheimer's disease brains. ER-mitochondria signaling is mediated by interactions between the integral ER protein VAPB and the outer mitochondrial membrane protein PTPIP51 which act to recruit and "tether" regions of ER to the mitochondrial surface. The VAPB-PTPIP51 tethers are now known to regulate a number of ER-mitochondria signaling functions including delivery of Ca
2+ from ER stores to mitochondria, mitochondrial ATP production, autophagy and synaptic activity. Here we investigate the VAPB-PTPIP51 tethers in post-mortem control and Alzheimer's disease brains. Quantification of ER-mitochondria signaling proteins by immunoblotting revealed loss of VAPB and PTPIP51 in cortex but not cerebellum at end-stage Alzheimer's disease. Proximity ligation assays were used to quantify the VAPB-PTPIP51 interaction in temporal cortex pyramidal neurons and cerebellar Purkinje cell neurons in control, Braak stage III-IV (early/mid-dementia) and Braak stage VI (severe dementia) cases. Pyramidal neurons degenerate in Alzheimer's disease whereas Purkinje cells are less affected. These studies revealed that the VAPB-PTPIP51 tethers are disrupted in Braak stage III-IV pyramidal but not Purkinje cell neurons. Thus, we identify a new pathogenic event in post-mortem Alzheimer's disease brains. The implications of our findings for Alzheimer's disease mechanisms are discussed., Competing Interests: Declaration of Competing Interest The authors declare they have no competing interests., (Copyright © 2020. Published by Elsevier Inc.)- Published
- 2020
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10. Kinesin light chain-1 serine-460 phosphorylation is altered in Alzheimer's disease and regulates axonal transport and processing of the amyloid precursor protein.
- Author
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Mórotz GM, Glennon EB, Greig J, Lau DHW, Bhembre N, Mattedi F, Muschalik N, Noble W, Vagnoni A, and Miller CCJ
- Subjects
- Aged, Aged, 80 and over, Alzheimer Disease genetics, Alzheimer Disease pathology, Amino Acid Sequence, Amyloid beta-Protein Precursor analysis, Amyloid beta-Protein Precursor genetics, Animals, Drosophila Proteins, Drosophila melanogaster, Female, Frontal Lobe chemistry, Frontal Lobe metabolism, Frontal Lobe pathology, HEK293 Cells, Humans, Kinesins, Male, Microtubule-Associated Proteins analysis, Microtubule-Associated Proteins genetics, Phosphorylation physiology, Rats, Serine analysis, Serine genetics, Alzheimer Disease metabolism, Amyloid beta-Protein Precursor biosynthesis, Axonal Transport physiology, Microtubule-Associated Proteins metabolism, Serine metabolism
- Abstract
Damage to axonal transport is an early pathogenic event in Alzheimer's disease. The amyloid precursor protein (APP) is a key axonal transport cargo since disruption to APP transport promotes amyloidogenic processing of APP. Moreover, altered APP processing itself disrupts axonal transport. The mechanisms that regulate axonal transport of APP are therefore directly relevant to Alzheimer's disease pathogenesis. APP is transported anterogradely through axons on kinesin-1 motors and one route for this transport involves calsyntenin-1, a type-1 membrane spanning protein that acts as a direct ligand for kinesin-1 light chains (KLCs). Thus, loss of calsyntenin-1 disrupts APP axonal transport and promotes amyloidogenic processing of APP. Phosphorylation of KLC1 on serine-460 has been shown to reduce anterograde axonal transport of calsyntenin-1 by inhibiting the KLC1-calsyntenin-1 interaction. Here we demonstrate that in Alzheimer's disease frontal cortex, KLC1 levels are reduced and the relative levels of KLC1 serine-460 phosphorylation are increased; these changes occur relatively early in the disease process. We also show that a KLC1 serine-460 phosphomimetic mutant inhibits axonal transport of APP in both mammalian neurons in culture and in Drosophila neurons in vivo. Finally, we demonstrate that expression of the KLC1 serine-460 phosphomimetic mutant promotes amyloidogenic processing of APP. Together, these results suggest that increased KLC1 serine-460 phosphorylation contributes to Alzheimer's disease.
- Published
- 2019
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11. LMTK2 binds to kinesin light chains to mediate anterograde axonal transport of cdk5/p35 and LMTK2 levels are reduced in Alzheimer's disease brains.
- Author
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Mórotz GM, Glennon EB, Gomez-Suaga P, Lau DHW, Robinson ED, Sedlák É, Vagnoni A, Noble W, and Miller CCJ
- Subjects
- Animals, HEK293 Cells, Humans, Kinesins, Neurons metabolism, Protein Binding, Rats, Adaptor Proteins, Signal Transducing metabolism, Alzheimer Disease metabolism, Axonal Transport, Brain metabolism, Cell Cycle Proteins metabolism, Cyclin-Dependent Kinase 5 metabolism, Membrane Proteins metabolism, Microtubule-Associated Proteins metabolism, Protein Serine-Threonine Kinases metabolism
- Abstract
Cyclin dependent kinase-5 (cdk5)/p35 is a neuronal kinase that regulates key axonal and synaptic functions but the mechanisms by which it is transported to these locations are unknown. Lemur tyrosine kinase-2 (LMTK2) is a binding partner for p35 and here we show that LMTK2 also interacts with kinesin-1 light chains (KLC1/2). Binding to KLC1/2 involves a C-terminal tryptophan/aspartate (WD) motif in LMTK2 and the tetratricopeptide repeat (TPR) domains in KLC1/2, and this interaction facilitates axonal transport of LMTK2. Thus, siRNA loss of KLC1 or mutation of the WD motif disrupts axonal transport of LMTK2. We also show that LMTK2 facilitates the formation of a complex containing KLC1 and p35 and that siRNA loss of LMTK2 disrupts axonal transport of both p35 and cdk5. Finally, we show that LMTK2 levels are reduced in Alzheimer's disease brains. Damage to axonal transport and altered cdk5/p35 are pathogenic features of Alzheimer's disease. Thus, LMTK2 binds to KLC1 to direct axonal transport of p35 and its loss may contribute to Alzheimer's disease.
- Published
- 2019
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12. The VAPB-PTPIP51 endoplasmic reticulum-mitochondria tethering proteins are present in neuronal synapses and regulate synaptic activity.
- Author
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Gómez-Suaga P, Pérez-Nievas BG, Glennon EB, Lau DHW, Paillusson S, Mórotz GM, Calì T, Pizzo P, Noble W, and Miller CCJ
- Subjects
- Animals, Cells, Cultured, Endoplasmic Reticulum chemistry, Hippocampus chemistry, Hippocampus metabolism, Kv Channel-Interacting Proteins analysis, Mitochondrial Proteins analysis, Neurons chemistry, Protein Tyrosine Phosphatases analysis, Rats, Synapses chemistry, Endoplasmic Reticulum metabolism, Kv Channel-Interacting Proteins metabolism, Mitochondrial Proteins metabolism, Neurons metabolism, Protein Tyrosine Phosphatases metabolism, Synapses metabolism
- Abstract
Signaling between the endoplasmic reticulum (ER) and mitochondria regulates a number of key neuronal functions. This signaling involves close physical contacts between the two organelles that are mediated by "tethering proteins" that function to recruit regions of ER to the mitochondrial surface. The ER protein, vesicle-associated membrane protein-associated protein B (VAPB) and the mitochondrial membrane protein, protein tyrosine phosphatase interacting protein-51 (PTPIP51), interact to form one such tether. Recently, damage to ER-mitochondria signaling involving disruption of the VAPB-PTPIP51 tethers has been linked to the pathogenic process in Parkinson's disease, fronto-temporal dementia (FTD) and related amyotrophic lateral sclerosis (ALS). Loss of neuronal synaptic function is a key feature of Parkinson's disease and FTD/ALS but the roles that ER-mitochondria signaling and the VAPB-PTPIP51 tethers play in synaptic function are not known. Here, we demonstrate that the VAPB-PTPIP51 tethers regulate synaptic activity. VAPB and PTPIP51 localise and form contacts at synapses, and stimulating neuronal activity increases ER-mitochondria contacts and the VAPB-PTPIP51 interaction. Moreover, siRNA loss of VAPB or PTPIP51 perturbs synaptic function and dendritic spine morphology. Our results reveal a new role for the VAPB-PTPIP51 tethers in neurons and suggest that damage to ER-mitochondria signaling contributes to synaptic dysfunction in Parkinson's disease and FTD/ALS.
- Published
- 2019
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13. Biological function of Lemur tyrosine kinase 2 (LMTK2): implications in neurodegeneration.
- Author
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Bencze J, Mórotz GM, Seo W, Bencs V, Kálmán J, Miller CCJ, and Hortobágyi T
- Subjects
- Animals, Apoptosis, Axonal Transport, Humans, Models, Biological, Protein Binding, Nerve Degeneration enzymology, Protein Serine-Threonine Kinases metabolism
- Abstract
Neurodegenerative disorders are frequent, incurable diseases characterised by abnormal protein accumulation and progressive neuronal loss. Despite their growing prevalence, the underlying pathomechanism remains unclear. Lemur tyrosine kinase 2 (LMTK2) is a member of a transmembrane serine/threonine-protein kinase family. Although it was described more than a decade ago, our knowledge on LMTK2's biological functions is still insufficient. Recent evidence has suggested that LMTK2 is implicated in neurodegeneration. After reviewing the literature, we identified three LMTK2-mediated mechanisms which may contribute to neurodegenerative processes: disrupted axonal transport, tau hyperphosphorylation and enhanced apoptosis. Moreover, LMTK2 gene expression is decreased in an Alzheimer's disease mouse model. According to these features, LMTK2 might be a promising therapeutic target in near future. However, further investigations are required to clarify the exact biological functions of this unique protein.
- Published
- 2018
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14. Disruption of ER-mitochondria signalling in fronto-temporal dementia and related amyotrophic lateral sclerosis.
- Author
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Lau DHW, Hartopp N, Welsh NJ, Mueller S, Glennon EB, Mórotz GM, Annibali A, Gomez-Suaga P, Stoica R, Paillusson S, and Miller CCJ
- Subjects
- Amyotrophic Lateral Sclerosis genetics, Animals, C9orf72 Protein genetics, C9orf72 Protein metabolism, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, Dementia genetics, Endoplasmic Reticulum genetics, Humans, Mitochondria genetics, Signal Transduction, Amyotrophic Lateral Sclerosis metabolism, Dementia metabolism, Endoplasmic Reticulum metabolism, Mitochondria metabolism
- Abstract
Fronto-temporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are two related and incurable neurodegenerative diseases. Features of these diseases include pathological protein inclusions in affected neurons with TAR DNA-binding protein 43 (TDP-43), dipeptide repeat proteins derived from the C9ORF72 gene, and fused in sarcoma (FUS) representing major constituent proteins in these inclusions. Mutations in C9ORF72 and the genes encoding TDP-43 and FUS cause familial forms of FTD/ALS which provides evidence to link the pathology and genetics of these diseases. A large number of seemingly disparate physiological functions are damaged in FTD/ALS. However, many of these damaged functions are regulated by signalling between the endoplasmic reticulum and mitochondria, and this has stimulated investigations into the role of endoplasmic reticulum-mitochondria signalling in FTD/ALS disease processes. Here, we review progress on this topic.
- Published
- 2018
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15. ER-mitochondria signaling regulates autophagy.
- Author
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Gomez-Suaga P, Paillusson S, and Miller CCJ
- Subjects
- Calcium metabolism, Membrane Proteins metabolism, Mitochondrial Proteins metabolism, Signal Transduction, Autophagy, Endoplasmic Reticulum metabolism, Mitochondria metabolism
- Abstract
The endoplasmic reticulum (ER) and mitochondria form tight functional contacts that regulate several key cellular processes. The formation of these contacts involves "tethering proteins" that function to recruit regions of ER to mitochondria. The integral ER protein VAPB (VAMP associated protein B and C) binds to the outer mitochondrial membrane protein, RMDN3/PTPIP51 (regulator of microtubule dynamics 3) to form one such set of tethers. Recently, we showed that the VAPB-RMDN3 tethers regulate macroautophagy/autophagy. Small interfering RNA (siRNA) knockdown of VAPB or RMDN3 to loosen ER-mitochondria contacts stimulates autophagosome formation, whereas overexpression of VAPB or RMDN3 to tighten contacts inhibit their formation. Artificial tethering of ER and mitochondria via expression of a synthetic linker protein also reduces autophagy and this artificial tether rescues the effects of VAPB- or RMDN3-targeted siRNA loss on autophagosome formation. Finally, our studies revealed that the modulatory effects of ER-mitochondria contacts on autophagy involve their role in mediating ITPR (inositol 1,4,5-trisphosphate receptor) delivery of Ca
2+ from ER stores to mitochondria.- Published
- 2017
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16. α-Synuclein binds to the ER-mitochondria tethering protein VAPB to disrupt Ca 2+ homeostasis and mitochondrial ATP production.
- Author
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Paillusson S, Gomez-Suaga P, Stoica R, Little D, Gissen P, Devine MJ, Noble W, Hanger DP, and Miller CCJ
- Subjects
- Animals, Cations, Divalent metabolism, Cell Line, Tumor, Dopaminergic Neurons metabolism, Dopaminergic Neurons pathology, Endoplasmic Reticulum metabolism, Endoplasmic Reticulum pathology, Glycogen Synthase Kinase 3 beta metabolism, HEK293 Cells, Humans, Induced Pluripotent Stem Cells metabolism, Induced Pluripotent Stem Cells pathology, Mitochondria pathology, Mitochondrial Proteins metabolism, Mutation, Parkinson Disease genetics, Parkinson Disease metabolism, Parkinson Disease pathology, Protein Tyrosine Phosphatases metabolism, Rats, Sprague-Dawley, alpha-Synuclein genetics, Adenosine Triphosphate metabolism, Calcium metabolism, Homeostasis physiology, Mitochondria metabolism, Vesicular Transport Proteins metabolism, alpha-Synuclein metabolism
- Abstract
α-Synuclein is strongly linked to Parkinson's disease but the molecular targets for its toxicity are not fully clear. However, many neuronal functions damaged in Parkinson's disease are regulated by signalling between the endoplasmic reticulum (ER) and mitochondria. This signalling involves close physical associations between the two organelles that are mediated by binding of the integral ER protein vesicle-associated membrane protein-associated protein B (VAPB) to the outer mitochondrial membrane protein, protein tyrosine phosphatase-interacting protein 51 (PTPIP51). VAPB and PTPIP51 thus act as a scaffold to tether the two organelles. Here we show that α-synuclein binds to VAPB and that overexpression of wild-type and familial Parkinson's disease mutant α-synuclein disrupt the VAPB-PTPIP51 tethers to loosen ER-mitochondria associations. This disruption to the VAPB-PTPIP51 tethers is also seen in neurons derived from induced pluripotent stem cells from familial Parkinson's disease patients harbouring pathogenic triplication of the α-synuclein gene. We also show that the α-synuclein induced loosening of ER-mitochondria contacts is accompanied by disruption to Ca
2+ exchange between the two organelles and mitochondrial ATP production. Such disruptions are likely to be particularly damaging to neurons that are heavily dependent on correct Ca2+ signaling and ATP.- Published
- 2017
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17. The ER-Mitochondria Tethering Complex VAPB-PTPIP51 Regulates Autophagy.
- Author
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Gomez-Suaga P, Paillusson S, Stoica R, Noble W, Hanger DP, and Miller CCJ
- Subjects
- Blood Proteins pharmacology, Calcium metabolism, Endoplasmic Reticulum drug effects, Gene Expression Regulation drug effects, HEK293 Cells, Humans, Immunosuppressive Agents pharmacology, Mitochondria drug effects, Mitochondrial Proteins antagonists & inhibitors, Mitochondrial Proteins genetics, Protein Tyrosine Phosphatases antagonists & inhibitors, Protein Tyrosine Phosphatases genetics, RNA, Small Interfering genetics, Sirolimus pharmacology, Starvation, Vesicular Transport Proteins antagonists & inhibitors, Vesicular Transport Proteins genetics, Autophagy, Endoplasmic Reticulum metabolism, Mitochondria metabolism, Mitochondrial Proteins metabolism, Protein Tyrosine Phosphatases metabolism, Vesicular Transport Proteins metabolism
- Abstract
Mitochondria form close physical associations with the endoplasmic reticulum (ER) that regulate a number of physiological functions. One mechanism by which regions of ER are recruited to mitochondria involves binding of the ER protein VAPB to the mitochondrial protein PTPIP51, which act as scaffolds to tether the two organelles. Here, we show that the VAPB-PTPIP51 tethers regulate autophagy. We demonstrate that overexpression of VAPB or PTPIP51 to tighten ER-mitochondria contacts impairs, whereas small interfering RNA (siRNA)-mediated loss of VAPB or PTPIP51 to loosen contacts stimulates, autophagosome formation. Moreover, we show that expression of a synthetic linker protein that artificially tethers ER and mitochondria also reduces autophagosome formation, and that this artificial tether rescues the effects of siRNA loss of VAPB or PTPIP51 on autophagy. Thus, these effects of VAPB and PTPIP51 manipulation on autophagy are a consequence of their ER-mitochondria tethering function. Interestingly, we discovered that tightening of ER-mitochondria contacts by overexpression of VAPB or PTPIP51 impairs rapamycin- and torin 1-induced, but not starvation-induced, autophagy. This suggests that the regulation of autophagy by ER-mitochondria signaling is at least partly dependent upon the nature of the autophagic stimulus. Finally, we demonstrate that the mechanism by which the VAPB-PTPIP51 tethers regulate autophagy involves their role in mediating delivery of Ca
2+ to mitochondria from ER stores. Thus, our findings reveal a new molecular mechanism for regulating autophagy., (Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.)- Published
- 2017
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18. There's Something Wrong with my MAM; the ER-Mitochondria Axis and Neurodegenerative Diseases.
- Author
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Paillusson S, Stoica R, Gomez-Suaga P, Lau DHW, Mueller S, Miller T, and Miller CCJ
- Subjects
- Animals, Endoplasmic Reticulum ultrastructure, Humans, Mitochondria ultrastructure, Neurodegenerative Diseases genetics, Neurodegenerative Diseases pathology, Neurodegenerative Diseases therapy, Endoplasmic Reticulum metabolism, Mitochondria metabolism, Neurodegenerative Diseases metabolism
- Abstract
Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis with associated frontotemporal dementia (ALS/FTD) are major neurodegenerative diseases for which there are no cures. All are characterised by damage to several seemingly disparate cellular processes. The broad nature of this damage makes understanding pathogenic mechanisms and devising new treatments difficult. Can the different damaged functions be linked together in a common disease pathway and which damaged function should be targeted for therapy? Many functions damaged in neurodegenerative diseases are regulated by communications that mitochondria make with a specialised region of the endoplasmic reticulum (ER; mitochondria-associated ER membranes or 'MAM'). Moreover, several recent studies have shown that disturbances to ER-mitochondria contacts occur in neurodegenerative diseases. Here, we review these findings., (Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2016
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19. Deregulation of PKN1 activity disrupts neurofilament organisation and axonal transport.
- Author
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Manser C, Stevenson A, Banner S, Davies J, Tudor EL, Ono Y, Leigh PN, McLoughlin DM, Shaw CE, and Miller CCJ
- Subjects
- Amyotrophic Lateral Sclerosis etiology, Amyotrophic Lateral Sclerosis genetics, Animals, Caspase 3 metabolism, Disease Models, Animal, Glutamic Acid toxicity, Humans, Male, Mice, Mice, Transgenic, Neurons drug effects, Neurons enzymology, Neurons ultrastructure, Protein Kinase C genetics, Rats, Spinal Cord metabolism, Superoxide Dismutase genetics, Superoxide Dismutase-1, Amyotrophic Lateral Sclerosis enzymology, Axonal Transport genetics, Neurofilament Proteins metabolism, Neurofilament Proteins ultrastructure, Protein Kinase C metabolism
- Abstract
Neurofilaments are synthesised in neuronal cell bodies and then transported through axons. Damage to neurofilament transport is seen in amyotrophic lateral sclerosis (ALS). Here, we show that PKN1, a neurofilament head-rod domain kinase is cleaved and activated in SOD1G93A transgenic mice that are a model of ALS. Moreover, we demonstrate that glutamate, a proposed toxic mechanism in ALS leads to caspase cleavage and disruption of PKN1 in neurons. Finally, we demonstrate that a cleaved form of PKN1 but not wild-type PKN1 disrupts neurofilament organisation and axonal transport. Thus, deregulation of PKN1 may contribute to the pathogenic process in ALS.
- Published
- 2008
- Full Text
- View/download PDF
20. Familial amyotrophic lateral sclerosis-linked SOD1 mutants perturb fast axonal transport to reduce axonal mitochondria content.
- Author
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De Vos KJ, Chapman AL, Tennant ME, Manser C, Tudor EL, Lau KF, Brownlees J, Ackerley S, Shaw PJ, McLoughlin DM, Shaw CE, Leigh PN, Miller CCJ, and Grierson AJ
- Subjects
- Amyotrophic Lateral Sclerosis genetics, Amyotrophic Lateral Sclerosis pathology, Animals, Female, Fluorescent Antibody Technique, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Mitochondria enzymology, Superoxide Dismutase metabolism, Superoxide Dismutase-1, Amyotrophic Lateral Sclerosis enzymology, Axonal Transport, Axons pathology, Mitochondria pathology, Mutation genetics, Superoxide Dismutase genetics
- Abstract
Amyotrophic lateral sclerosis (ALS) is a late-onset neurological disorder characterized by death of motoneurons. Mutations in Cu/Zn superoxide dismutase-1 (SOD1) cause familial ALS but the mechanisms whereby they induce disease are not fully understood. Here, we use time-lapse microscopy to monitor for the first time the effect of mutant SOD1 on fast axonal transport (FAT) of bona fide cargoes in living neurons. We analyzed FAT of mitochondria that are a known target for damage by mutant SOD1 and also of membrane-bound organelles (MBOs) using EGFP-tagged amyloid precursor protein as a marker. We studied FAT in motor neurons derived from SOD1G93A transgenic mice that are a model of ALS and also in cortical neurons transfected with SOD1G93A and three further ALS-associated SOD1 mutants. We find that mutant SOD1 damages transport of both mitochondria and MBOs, and that the precise details of this damage are cargo-specific. Thus, mutant SOD1 reduces transport of MBOs in both anterograde and retrograde directions, whereas mitochondrial transport is selectively reduced in the anterograde direction. Analyses of the characteristics of mitochondrial FAT revealed that reduced anterograde movement involved defects in anterograde motor function. The selective inhibition of anterograde mitochondrial FAT enhanced their net retrograde movement to deplete mitochondria in axons. Mitochondria in mutant SOD1 expressing cells also displayed features of damage. Together, such changes to mitochondrial function and distribution are likely to compromise axonal function. These alterations represent some of the earliest pathological features so far reported in neurons of mutant SOD1 transgenic mice.
- Published
- 2007
- Full Text
- View/download PDF
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