Bauer, C.S., Webster, C.P., Shaw, A.C. et al. (12 more authors) (2022) Loss of TMEM106B exacerbates C9ALS/FTD DPR pathology by disrupting autophagosome maturation. Frontiers in Cellular Neuroscience, 16. 1061559. ISSN 1662-5102
Abstract
Disruption to protein homeostasis caused by lysosomal dysfunction and associated impairment of autophagy is a prominent pathology in amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). The most common genetic cause of ALS/FTD is a G4C2 hexanucleotide repeat expansion in C9orf72 (C9ALS/FTD). Repeat-associated non-AUG (RAN) translation of G4C2 repeat transcripts gives rise to dipeptide repeat (DPR) proteins that have been shown to be toxic and may contribute to disease etiology. Genetic variants in TMEM106B have been associated with frontotemporal lobar degeneration with TDP-43 pathology and disease progression in C9ALS/FTD. TMEM106B encodes a lysosomal transmembrane protein of unknown function that is involved in various aspects of lysosomal biology. How TMEM106B variants affect C9ALS/FTD is not well understood but has been linked to changes in TMEM106B protein levels. Here, we investigated TMEM106B function in the context of C9ALS/FTD DPR pathology. We report that knockdown of TMEM106B expression exacerbates the accumulation of C9ALS/FTD-associated cytotoxic DPR proteins in cell models expressing RAN-translated or AUG-driven DPRs as well as in C9ALS/FTD-derived iAstrocytes with an endogenous G4C2 expansion by impairing autophagy. Loss of TMEM106B caused a block late in autophagy by disrupting autophagosome to autolysosome maturation which coincided with impaired lysosomal acidification, reduced cathepsin activity, and juxtanuclear clustering of lysosomes. Lysosomal clustering required Rab7A and coincided with reduced Arl8b-mediated anterograde transport of lysosomes to the cell periphery. Increasing Arl8b activity in TMEM106B-deficient cells not only restored the distribution of lysosomes, but also fully rescued autophagy and DPR protein accumulation. Thus, we identified a novel function of TMEM106B in autophagosome maturation via Arl8b. Our findings indicate that TMEM106B variants may modify C9ALS/FTD by regulating autophagic clearance of DPR proteins. Caution should therefore be taken when considering modifying TMEM106B expression levels as a therapeutic approach in ALS/FTD.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2022 Bauer, Webster, Shaw, Kok, Castelli, Lin, Smith, Illanes-Álvarez, Higginbottom, Shaw, Azzouz, Ferraiuolo, Hautbergue, Grierson and De Vos. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms (https://creativecommons.org/licenses/by/4.0/) |
Keywords: | C9orf72; DPR; autophagy; ALS/FTD; TMEM106B |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Sheffield Teaching Hospitals The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Department of Neuroscience (Sheffield) |
Funding Information: | Funder Grant number MOTOR NEURONE DISEASE ASSOCIATION DeVos/Apr18/862-791 ALZHEIMER'S SOCIETY 260 (AS-PG-15-023) Motor Neurone Disease Association DeVos/Oct13/870-792 MEDICAL RESEARCH COUNCIL MR/M013251/1 MEDICAL RESEARCH COUNCIL MR/S025979/1 Motor Neurone Disease Association MNDA-DeVos/Apr18/862-791 Motor Neurone Disease Association MNDA-DeVos/Oct13/870-792 |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 20 Dec 2022 10:46 |
Last Modified: | 20 Dec 2022 10:46 |
Status: | Published |
Publisher: | Frontiers Media SA |
Refereed: | Yes |
Identification Number: | 10.3389/fncel.2022.1061559 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:194626 |