dc.contributor.author |
Wu, Josephine J |
|
dc.contributor.author |
Cai, Ashley |
|
dc.contributor.author |
Greenslade, Jessie E |
|
dc.contributor.author |
Higgins, Nicole R |
|
dc.contributor.author |
Fan, Cong |
|
dc.contributor.author |
Le, Nhat TT |
|
dc.contributor.author |
Tatman, Micaela |
|
dc.contributor.author |
Whiteley, Alexandra M |
|
dc.contributor.author |
Prado, Miguel A |
|
dc.contributor.author |
Dieriks, Birger V |
|
dc.contributor.author |
Curtis, Maurice A |
|
dc.contributor.author |
Shaw, Christopher E |
|
dc.contributor.author |
Siddique, Teepu |
|
dc.contributor.author |
Faull, Richard LM |
|
dc.contributor.author |
Scotter, Emma L |
|
dc.contributor.author |
Finley, Daniel |
|
dc.contributor.author |
Monteiro, Mervyn J |
|
dc.coverage.spatial |
United States |
|
dc.date.accessioned |
2023-09-11T02:30:18Z |
|
dc.date.available |
2023-09-11T02:30:18Z |
|
dc.date.issued |
2020-06 |
|
dc.identifier.citation |
(2020). Proceedings of the National Academy of Sciences of USA, 117(26), 15230-15241. |
|
dc.identifier.issn |
0027-8424 |
|
dc.identifier.uri |
https://hdl.handle.net/2292/65714 |
|
dc.description.abstract |
Mutations in <i>UBQLN2</i> cause amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and other neurodegenerations. However, the mechanism by which the UBQLN2 mutations cause disease remains unclear. Alterations in proteins involved in autophagy are prominent in neuronal tissue of human ALS <i>UBQLN2</i> patients and in a transgenic P497S UBQLN2 mouse model of ALS/FTD, suggesting a pathogenic link. Here, we show UBQLN2 functions in autophagy and that ALS/FTD mutant proteins compromise this function. Inactivation of UBQLN2 expression in HeLa cells reduced autophagic flux and autophagosome acidification. The defect in acidification was rescued by reexpression of wild type (WT) UBQLN2 but not by any of the five different UBQLN2 ALS/FTD mutants tested. Proteomic analysis and immunoblot studies revealed P497S mutant mice and UBQLN2 knockout HeLa and NSC34 cells have reduced expression of ATP6v1g1, a critical subunit of the vacuolar ATPase (V-ATPase) pump. Knockout of UBQLN2 expression in HeLa cells decreased turnover of ATP6v1g1, while overexpression of WT UBQLN2 increased biogenesis of ATP6v1g1 compared with P497S mutant UBQLN2 protein. In vitro interaction studies showed that ATP6v1g1 binds more strongly to WT UBQLN2 than to ALS/FTD mutant UBQLN2 proteins. Intriguingly, overexpression of ATP6v1g1 in UBQLN2 knockout HeLa cells increased autophagosome acidification, suggesting a therapeutic approach to overcome the acidification defect. Taken together, our findings suggest that UBQLN2 mutations drive pathogenesis through a dominant-negative loss-of-function mechanism in autophagy and that UBQLN2 functions as an important regulator of the expression and stability of ATP6v1g1. These findings may have important implications for devising therapies to treat <i>UBQLN2</i>-linked ALS/FTD. |
|
dc.format.medium |
Print-Electronic |
|
dc.language |
eng |
|
dc.publisher |
Proceedings of the National Academy of Sciences |
|
dc.relation.ispartofseries |
Proceedings of the National Academy of Sciences of the United States of America |
|
dc.rights |
Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher. |
|
dc.rights.uri |
https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm |
|
dc.subject |
Cell Line |
|
dc.subject |
Animals |
|
dc.subject |
Mice, Transgenic |
|
dc.subject |
Humans |
|
dc.subject |
Mice |
|
dc.subject |
Dementia |
|
dc.subject |
Amyotrophic Lateral Sclerosis |
|
dc.subject |
Genetic Predisposition to Disease |
|
dc.subject |
Vacuolar Proton-Translocating ATPases |
|
dc.subject |
Adaptor Proteins, Signal Transducing |
|
dc.subject |
Microtubule-Associated Proteins |
|
dc.subject |
Up-Regulation |
|
dc.subject |
Protein Binding |
|
dc.subject |
Mutation |
|
dc.subject |
Hydrogen-Ion Concentration |
|
dc.subject |
Autophagy |
|
dc.subject |
Lysosome-Associated Membrane Glycoproteins |
|
dc.subject |
Biomarkers |
|
dc.subject |
Sequestosome-1 Protein |
|
dc.subject |
Autophagy-Related Proteins |
|
dc.subject |
Autophagosomes |
|
dc.subject |
UBQLN2 |
|
dc.subject |
ubiquilin |
|
dc.subject |
vacuolar ATPase pump |
|
dc.subject |
3101 Biochemistry and Cell Biology |
|
dc.subject |
31 Biological Sciences |
|
dc.subject |
Neurodegenerative |
|
dc.subject |
Rare Diseases |
|
dc.subject |
ALS |
|
dc.subject |
Brain Disorders |
|
dc.subject |
Neurosciences |
|
dc.subject |
2 Aetiology |
|
dc.subject |
2.1 Biological and endogenous factors |
|
dc.subject |
Neurological |
|
dc.subject |
Science & Technology |
|
dc.subject |
Multidisciplinary Sciences |
|
dc.subject |
Science & Technology - Other Topics |
|
dc.subject |
UBIQUITIN-LIKE PROTEIN |
|
dc.subject |
H+-ATPASE |
|
dc.subject |
V-ATPASE |
|
dc.subject |
INTERMEDIATE-FILAMENTS |
|
dc.subject |
MOLECULAR-CLONING |
|
dc.subject |
MOUSE MODEL |
|
dc.subject |
DEGRADATION |
|
dc.subject |
CHAPERONE |
|
dc.subject |
BINDS |
|
dc.title |
ALS/FTD mutations in UBQLN2 impede autophagy by reducing autophagosome acidification through loss of function. |
|
dc.type |
Journal Article |
|
dc.identifier.doi |
10.1073/pnas.1917371117 |
|
pubs.issue |
26 |
|
pubs.begin-page |
15230 |
|
pubs.volume |
117 |
|
dc.date.updated |
2023-08-07T02:32:05Z |
|
dc.rights.holder |
Copyright: 2023 National Academy of Science |
en |
dc.identifier.pmid |
32513711 (pubmed) |
|
pubs.author-url |
https://www.ncbi.nlm.nih.gov/pubmed/32513711 |
|
pubs.end-page |
15241 |
|
pubs.publication-status |
Published |
|
dc.rights.accessrights |
http://purl.org/eprint/accessRights/RetrictedAccess |
en |
pubs.subtype |
Research Support, Non-U.S. Gov't |
|
pubs.subtype |
research-article |
|
pubs.subtype |
Journal Article |
|
pubs.subtype |
Research Support, N.I.H., Extramural |
|
pubs.elements-id |
805527 |
|
pubs.org-id |
Medical and Health Sciences |
|
pubs.org-id |
Science |
|
pubs.org-id |
Biological Sciences |
|
pubs.org-id |
Medical Sciences |
|
pubs.org-id |
Anatomy and Medical Imaging |
|
dc.identifier.eissn |
1091-6490 |
|
dc.identifier.pii |
1917371117 |
|
pubs.record-created-at-source-date |
2023-08-07 |
|
pubs.online-publication-date |
2020-06-08 |
|