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402 results on '"Lin, Wen Lang"'

1. C9ORF72 poly(GA) aggregates sequester and impair HR23 and nucleocytoplasmic transport proteins

Author

Zhang, Yong-Jie, Gendron, Tania F, Grima, Jonathan C, Sasaguri, Hiroki, Jansen-West, Karen, Xu, Ya-Fei, Katzman, Rebecca B, Gass, Jennifer, Murray, Melissa E, Shinohara, Mitsuru, Lin, Wen-Lang, Garrett, Aliesha, Stankowski, Jeannette N, Daughrity, Lillian, Tong, Jimei, Perkerson, Emilie A, Yue, Mei, Chew, Jeannie, Castanedes-Casey, Monica, Kurti, Aishe, Wang, Zizhao S, Liesinger, Amanda M, Baker, Jeremy D, Jiang, Jie, Lagier-Tourenne, Clotilde, Edbauer, Dieter, Cleveland, Don W, Rademakers, Rosa, Boylan, Kevin B, Bu, Guojun, Link, Christopher D, Dickey, Chad A, Rothstein, Jeffrey D, Dickson, Dennis W, Fryer, John D, and Petrucelli, Leonard

Subjects
Acquired Cognitive Impairment, Brain Disorders, Neurodegenerative, Dementia, Amyotrophic Lateral Sclerosis, Animals, Atrophy, Behavior, Animal, Brain, C9orf72 Protein, Carrier Proteins, DNA-Binding Proteins, Frontotemporal Dementia, Gene Expression, Guanine Nucleotide Exchange Factors, Humans, Inclusion Bodies, Mice, Mutation, Nerve Degeneration, Neurons, Primary Cell Culture, Proteins, Ubiquitinated Proteins, Neurosciences, Psychology, Cognitive Sciences, Neurology & Neurosurgery
Abstract

Neuronal inclusions of poly(GA), a protein unconventionally translated from G4C2 repeat expansions in C9ORF72, are abundant in patients with frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) caused by this mutation. To investigate poly(GA) toxicity, we generated mice that exhibit poly(GA) pathology, neurodegeneration and behavioral abnormalities reminiscent of FTD and ALS. These phenotypes occurred in the absence of TDP-43 pathology and required poly(GA) aggregation. HR23 proteins involved in proteasomal degradation and proteins involved in nucleocytoplasmic transport were sequestered by poly(GA) in these mice. HR23A and HR23B similarly colocalized to poly(GA) inclusions in C9ORF72 expansion carriers. Sequestration was accompanied by an accumulation of ubiquitinated proteins and decreased xeroderma pigmentosum C (XPC) levels in mice, indicative of HR23A and HR23B dysfunction. Restoring HR23B levels attenuated poly(GA) aggregation and rescued poly(GA)-induced toxicity in neuronal cultures. These data demonstrate that sequestration and impairment of nuclear HR23 and nucleocytoplasmic transport proteins is an outcome of, and a contributor to, poly(GA) pathology.

Published
2016

2. Heterochromatin anomalies and double-stranded RNA accumulation underlie C9orf72 poly(PR) toxicity

Author

Zhang, Yong-Jie, Guo, Lin, Gonzales, Patrick K., Gendron, Tania F., Wu, Yanwei, Jansen-West, Karen, O’Raw, Aliesha D., Pickles, Sarah R., Prudencio, Mercedes, Carlomagno, Yari, Gachechiladze, Mariam A., Ludwig, Connor, Tian, Ruilin, Chew, Jeannie, DeTure, Michael, Lin, Wen-Lang, Tong, Jimei, Daughrity, Lillian M., Yue, Mei, Song, Yuping, Andersen, Jonathan W., Castanedes-Casey, Monica, Kurti, Aishe, Datta, Abhishek, Antognetti, Giovanna, McCampbell, Alexander, Rademakers, Rosa, Oskarsson, Björn, Dickson, Dennis W., Kampmann, Martin, Ward, Michael E., Fryer, John D., Link, Christopher D., Shorter, James, and Petrucelli, Leonard

Published
2019

3. LRRK2 knockout mice have an intact dopaminergic system but display alterations in exploratory and motor co-ordination behaviors

Author

Hinkle, Kelly M, Yue, Mei, Behrouz, Bahareh, Dächsel, Justus C, Lincoln, Sarah J, Bowles, Erin E, Beevers, Joel E, Dugger, Brittany, Winner, Beate, Prots, Iryna, Kent, Caroline B, Nishioka, Kenya, Lin, Wen-Lang, Dickson, Dennis W, Janus, Christopher J, Farrer, Matthew J, and Melrose, Heather L

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Neurosciences, Biological Sciences, Brain Disorders, Parkinson's Disease, Behavioral and Social Science, Aging, Neurodegenerative, Genetics, Aetiology, 2.1 Biological and endogenous factors, Neurological, Animals, Autophagy, Behavior, Animal, Dopamine, Kidney, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Mice, Mice, Inbred C57BL, Mice, Knockout, Mutation, Neurons, Parkinson Disease, Protein Serine-Threonine Kinases, Parkinson's disease, Knockout, Microdialysis, Neuropathology, Open-field, Motor coordination, Protein-Serine-Threonine Kinases, Clinical Sciences, Neurology & Neurosurgery, Biochemistry and cell biology
Abstract

Mutations in the LRRK2 gene are the most common cause of genetic Parkinson's disease. Although the mechanisms behind the pathogenic effects of LRRK2 mutations are still not clear, data emerging from in vitro and in vivo models suggests roles in regulating neuronal polarity, neurotransmission, membrane and cytoskeletal dynamics and protein degradation.We created mice lacking exon 41 that encodes the activation hinge of the kinase domain of LRRK2. We have performed a comprehensive analysis of these mice up to 20 months of age, including evaluation of dopamine storage, release, uptake and synthesis, behavioral testing, dendritic spine and proliferation/neurogenesis analysis.Our results show that the dopaminergic system was not functionally comprised in LRRK2 knockout mice. However, LRRK2 knockout mice displayed abnormal exploratory activity in the open-field test. Moreover, LRRK2 knockout mice stayed longer than their wild type littermates on the accelerated rod during rotarod testing. Finally, we confirm that loss of LRRK2 caused degeneration in the kidney, accompanied by a progressive enhancement of autophagic activity and accumulation of autofluorescent material, but without evidence of biphasic changes.

Published
2012

5. Vascular Collagen Type-IV in Hypertension and Cerebral Small Vessel Disease.

Author

Kumar, Apoorva A., Yeo, Natalie, Whittaker, Max, Attra, Priya, Barrick, Thomas R., Bridges, Leslie R., Dickson, Dennis W., Esiri, Margaret M., Farris, Chad W., Graham, Delyth, Lin, Wen Lang, Meijles, Daniel N., Pereira, Anthony C., Perry, Gregory, Rosene, Douglas L., Shtaya, Anan B., Van Agtmael, Tom, Zamboni, Giovanna, and Hainsworth, Atticus H.

Published
2023
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6. ALS/FTD Mutation-Induced Phase Transition of FUS Liquid Droplets and Reversible Hydrogels into Irreversible Hydrogels Impairs RNP Granule Function

Author

Murakami, Tetsuro, Qamar, Seema, Lin, Julie Qiaojin, Schierle, Gabriele S. Kaminski, Rees, Eric, Miyashita, Akinori, Costa, Ana R., Dodd, Roger B., Chan, Fiona T.S., Michel, Claire H., Kronenberg-Versteeg, Deborah, Li, Yi, Yang, Seung-Pil, Wakutani, Yosuke, Meadows, William, Ferry, Rodylyn Rose, Dong, Liang, Tartaglia, Gian Gaetano, Favrin, Giorgio, Lin, Wen-Lang, Dickson, Dennis W., Zhen, Mei, Ron, David, Schmitt-Ulms, Gerold, Fraser, Paul E., Shneider, Neil A., Holt, Christine, Vendruscolo, Michele, Kaminski, Clemens F., and St George-Hyslop, Peter

Published
2015
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7. Vascular Collagen Type-IV in Hypertension and Cerebral Small Vessel Disease

Author

Kumar, Apoorva A., primary, Yeo, Natalie, additional, Whittaker, Max, additional, Attra, Priya, additional, Barrick, Thomas R., additional, Bridges, Leslie R., additional, Dickson, Dennis W., additional, Esiri, Margaret M., additional, Farris, Chad W., additional, Graham, Delyth, additional, Lin, Wen Lang, additional, Meijles, Daniel N., additional, Pereira, Anthony C., additional, Perry, Gregory, additional, Rosene, Douglas L., additional, Shtaya, Anan B., additional, Van Agtmael, Tom, additional, Zamboni, Giovanna, additional, and Hainsworth, Atticus H., additional

Published
2022
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10. A novel tau mutation, p.K317N, causes globular glial tauopathy

Author

Tacik, Pawel, DeTure, Michael, Lin, Wen-Lang, Sanchez Contreras, Monica, Wojtas, Aleksandra, Hinkle, Kelly M., Fujioka, Shinsuke, Baker, Matthew C., Walton, Ronald L., Carlomagno, Yari, Brown, Patricia H., Strongosky, Audrey J., Kouri, Naomi, Murray, Melissa E., Petrucelli, Leonard, Josephs, Keith A., Rademakers, Rosa, Ross, Owen A., Wszolek, Zbigniew K., and Dickson, Dennis W.

Published
2015
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13. Aberrant Cleavage of TDP-43 Enhances Aggregation and Cellular Toxicity

Author

Zhang, Yong-Jie, Xu, Ya-Fei, Cook, Casey, Gendron, Tania F., Roettges, Paul, Link, Christopher D., Lin, Wen-Lang, Tong, Jimei, Castanedes-Casey, Monica, Ash, Peter, Gass, Jennifer, Rangachari, Vijayaraghavan, Buratti, Emanuele, Baralle, Francisco, Golde, Todd E., Dickson, Dennis W., Petrucelli, Leonard, and Snyder, Solomon H.

Published
2009
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15. Aggregation-prone c9FTD/ALS poly(GA) RAN-translated proteins cause neurotoxicity by inducing ER stress

Author

Zhang, Yong-Jie, Jansen-West, Karen, Xu, Ya-Fei, Gendron, Tania F., Bieniek, Kevin F., Lin, Wen-Lang, Sasaguri, Hiroki, Caulfield, Thomas, Hubbard, Jaime, Daughrity, Lillian, Chew, Jeannie, Belzil, Veronique V., Prudencio, Mercedes, Stankowski, Jeannette N., Castanedes-Casey, Monica, Whitelaw, Ena, Ash, Peter E. A., DeTure, Michael, Rademakers, Rosa, Boylan, Kevin B., Dickson, Dennis W., and Petrucelli, Leonard

Published
2014
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26. Neuronal intermediate filament inclusion disease may be incorrectly classified as a subtype of FTLD-FUS

Author

Bieniek, Kevin F., Josephs, Keith A., Lin, Wen-Lang, and Dickson, Dennis W.

Subjects
TDP-43, mental disorders, NIFID, Atypical frontotemporal lobar degeneration, Electron microscope, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Article, nervous system diseases, FUS, lcsh:RC321-571
Abstract

Background: The majority of cases of frontotemporal lobar degeneration (FTLD) are characterized by focal cortical atrophy with an underlying tau or TDP-43 proteinopathy. A subset of FTLD cases, however, lack tau and TDP-43 immunoreactivity, but have neuronal inclusions positive for ubiquitin, referred to as atypical FTLD (aFTLD-U). Studies have demonstrated that ubiquitin-positive inclusions in aFTLD-U are immunoreactive for fused in sarcoma (FUS). As such, the current nosology for this entity is FTLD-FUS, which is thought to include not only aFTLD-U but also neuronal intermediate filament inclusion disease (NIFID) and basophilic inclusion body disease. Objective: To compare pathological features of cases of aFTLD-U and NIFID. Methods: We reviewed the neuropathology of 15 patients (10 males and 5 females; average age at death 54 years (range 41-69 years)) with an antemortem clinical diagnosis of a frontotemporal dementia and pathological diagnosis of aFTLD-U (n=8) or NIFID (n=7). Sections were processed for immunohistochemistry and immunoelectron microscopy with FUS, TDP-43, and α-internexin (αINX) antibodies. Results: Eight cases had pathologic features consistent with FTLD-FUS, with severe striatal atrophy (7/8 cases), as well as FUS-positive neuronal cytoplasmic and vermiform intranuclear inclusions, but no αINX immunoreactivity. Five cases had features consistent with NIFID, with neuronal inclusions positive for both FUS and αINX. Striatal atrophy was present in only two of the NIFID cases. Two cases had αINX-positive neuronal inclusions consistent with NIFID, but both lacked striatal atrophy and FUS immunoreactivity. Surprisingly, one of these two NIFID cases had lesions immunoreactive for TDP-43. Discussion: While FUS pathology remains a prominent feature of aFTLD-U, there is pathologic heterogeneity, including rare cases of NIFID with TDP-43- rather than FUS-positive inclusions., Free Neuropathology, Bd. 1 (2020)

Published
2020

27. Mitophagy alterations in Alzheimer's disease are associated with granulovacuolar degeneration and early tau pathology

Author

Hou, Xu, Watzlawik, Jens O., Cook, Casey, Liu, Chia-Chen, Kang, Silvia S., Lin, Wen-Lang, DeTure, Michael, Heckman, Michael G., Diehl, Nancy N., Al-Shaikh, Fadi S. Hanna, Walton, Ronald L., Ross, Owen A., Melrose, Heather L., Ertekin-Taner, Nilüfer, Bu, Guojun, Petrucelli, Leonard, Fryer, John D., Murray, Melissa E., Dickson, Dennis W., Fiesel, Fabienne C., Springer, Wolfdieter, Hou, Xu, Watzlawik, Jens O., Cook, Casey, Liu, Chia-Chen, Kang, Silvia S., Lin, Wen-Lang, DeTure, Michael, Heckman, Michael G., Diehl, Nancy N., Al-Shaikh, Fadi S. Hanna, Walton, Ronald L., Ross, Owen A., Melrose, Heather L., Ertekin-Taner, Nilüfer, Bu, Guojun, Petrucelli, Leonard, Fryer, John D., Murray, Melissa E., Dickson, Dennis W., Fiesel, Fabienne C., and Springer, Wolfdieter

Abstract

Introduction: The cytoprotective PTEN-induced kinase 1 (PINK1)-parkin RBR E3 ubiquitin protein ligase (PRKN) pathway selectively labels damaged mitochondria with phosphorylated ubiquitin (pS65-Ub) for their autophagic removal (mitophagy). Because dysfunctions of mitochondria and degradation pathways are early features of Alzheimer's disease (AD), mitophagy impairments may contribute to the pathogenesis. Methods: Morphology, levels, and distribution of the mitophagy tag pS65-Ub were evaluated by biochemical analyses combined with tissue and single cell imaging in AD autopsy brain and in transgenic mouse models. Results: Analyses revealed significant increases of pS65-Ub levels in AD brain, which strongly correlated with granulovacuolar degeneration (GVD) and early phospho-tau deposits, but were independent of amyloid beta pathology. Single cell analyses revealed predominant co-localization of pS65-Ub with mitochondria, GVD bodies, and/or lysosomes depending on the brain region analyzed. Discussion: Our study highlights mitophagy alterations in AD that are associated with early tau pathology, and suggests that distinct mitochondrial, autophagic, and/or lysosomal failure may contribute to the selective vulnerability in disease. © 2020 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.

Published
2021

31. Growth of beta-amyloid(1-40) protofibrils by monomer elongation and lateral association. Characterization of distinct products by light scattering and atomic force microscopy

Author

Nichols, Michael R., Moss, Melissa A., Reed, Dana Kim, Lin, Wen-Lang, Mukhopadhyay, Rajendrani, Hoh, Jan H., and Rosenberry, Terrone L.

Subjects
Biochemistry -- Research, Amyloid beta-protein -- Physiological aspects, Monomers -- Physiological aspects, Atomic force microscopy -- Usage, Light scattering -- Research, Growth -- Research, Biological sciences, Chemistry
Abstract

Research has been conducted on the brain tussie amyloid plaques composed of interwoven fibrils. Results indicate that protofibril growth by the monomer deposition can been investigated via the structural analysis and ionic strength dependence.

Published
2002

34. Mitophagy alterations in Alzheimer's disease are associated with granulovacuolar degeneration and early tau pathology

Author

Hou, Xu, primary, Watzlawik, Jens O., additional, Cook, Casey, additional, Liu, Chia‐Chen, additional, Kang, Silvia S., additional, Lin, Wen‐Lang, additional, DeTure, Michael, additional, Heckman, Michael G., additional, Diehl, Nancy N., additional, Al‐Shaikh, Fadi S. Hanna, additional, Walton, Ronald L., additional, Ross, Owen A., additional, Melrose, Heather L., additional, Ertekin‐Taner, Nilüfer, additional, Bu, Guojun, additional, Petrucelli, Leonard, additional, Fryer, John D., additional, Murray, Melissa E., additional, Dickson, Dennis W., additional, Fiesel, Fabienne C., additional, and Springer, Wolfdieter, additional

Published
2020
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