Cited by 86Autophagy in Disease and TherapyAmyotrophic Lateral Sclerosis ResearchAlzheimer's disease research and treatments

ALS/FTD mutations in UBQLN2 impede autophagy by reducing autophagosome acidification through loss of function

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Wu, Josephine J., Cai, Ashley, Greenslade, Jessie E., Higgins, Nicole R., Fan, Cong, Le, Nhat T. T., Tatman, Micaela, Whiteley, Alexandra M. +9 more·2020·Proceedings of the National Academy of Sciences

Abstract

Significance: Mutations in UBQLN2 cause amyotrophic lateral sclerosis with frontotemporal dementia (ALS/FTD). UBQLN2 regulates proteostasis by clearing misfolded proteins from cells through the proteasome and autophagy degradation pathways. Here, we report on defects in autophagy that results from knockout or expression of WT and ALS/FTD mutant UBQLN2 proteins in cells and mice. We show that loss of UBQLN2 reduces expression of ATP6v1g1, a critical subunit of the ATPase pump that regulates vacuolar acidification and is required for the maturation of autophagosomes. We show that WT but not ALS/FTD mutant UBQLN2 proteins can rescue the acidification defect. Furthermore, WT but not ALS/FTD mutant UBQLN2 proteins bind and stimulate ATP6v1g1 biogenesis, suggesting an important role played by UBQLN2 in V-ATPase regulation.

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Crossref · 10.1073/pnas.1917371117

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Authors
Wu, J. J., Cai, A., Greenslade, J. E., Higgins, N. R., Fan, C., Le, N. T. T., Tatman, M., Whiteley, A. M., Prado, M. A., Dieriks, B. V., Curtis, M. A., Shaw, C. E., Siddique, T., Faull, R. L. M., Scotter, E. L., Finley, D., & Monteiro, M. J.
Affiliations
  • University of Maryland, Baltimore (US)
  • Harvard University (US)
  • University of Auckland (NZ)
  • King's College London (GB)
  • Northwestern University (US)
Corresponding author
Monteiro, Mervyn J.
Venue
Proceedings of the National Academy of Sciences
Published
2020-06-08
Volume
117
Issue
26
Pages
15230-15241
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
OpenAlex
W3033186313
Cited by
86
References
76
Citations by year
2026: 7 · 2025: 12 · 2024: 15 · 2023: 17 · 2022: 15 · 2021: 12 · 2020: 8
FWCI
9.32
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Research Portal (King's College London) (submittedVersion)
  • ResearchSpace (University of Auckland) (submittedVersion)
Funders
  • HHS | NIH | National Institute of Neurological Disorders and Stroke (R01NS098243, R01NS100008, R01NS078504, R01NS046535)
  • The Robert Packard Center for ALS Research at Johns Hopkins (17-IIP-356-1)
  • The ALS Association (17-IIP-356-1)
Topics
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Keywords
UBQLN2, amyotrophic lateral sclerosis, frontotemporal dementia, autophagy, V-ATPase, proteostasis, protein misfolding, loss-of-function mutations, autophagosome maturation, proteasome
MeSH terms
Autophagosomes, Autophagy-Related Proteins, Sequestosome-1 Protein, Amyotrophic Lateral Sclerosis, Animals, Autophagy, Cell Line, Dementia, Humans, Hydrogen-Ion Concentration, Mice, Transgenic, Microtubule-Associated Proteins, Mutation, Protein Binding, Biomarkers, Up-Regulation, Genetic Predisposition to Disease, Vacuolar Proton-Translocating ATPases, Adaptor Proteins, Signal Transducing, Mice, Lysosomal Membrane Proteins, Lysosomal-Associated Membrane Protein 1

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