Pathogenic mutations in UBQLN2 exhibit diverse aggregation propensity and neurotoxicity.
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
13 Mar 2024
13 Mar 2024
Historique:
received:
02
11
2023
accepted:
26
02
2024
medline:
13
3
2024
pubmed:
13
3
2024
entrez:
13
3
2024
Statut:
epublish
Résumé
The ubiquitin-adaptor protein UBQLN2 promotes degradation of several aggregate-prone proteins implicated in neurodegenerative diseases. Missense UBQLN2 mutations also cause X-linked amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Previously we demonstrated that the liquid-like properties of UBQLN2 molecular assemblies are altered by a specific pathogenic mutation, P506T, and that the propensity of UBQLN2 to aggregate correlated with neurotoxicity. Here, we systematically assess the effects of multiple, spatially distinct ALS/FTD-linked missense mutations on UBQLN2 aggregation propensity, neurotoxicity, phase separation, and autophagic flux. In contrast to what we observed for the P506T mutation, no other tested pathogenic mutant exhibited a clear correlation between aggregation propensity and neurotoxicity. These results emphasize the unique nature of pathogenic UBQLN2 mutations and argue against a generalizable link between aggregation propensity and neurodegeneration in UBQLN2-linked ALS/FTD.
Identifiants
pubmed: 38472280
doi: 10.1038/s41598-024-55582-9
pii: 10.1038/s41598-024-55582-9
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
6049Subventions
Organisme : NIH HHS
ID : R01NS097542-01
Pays : United States
Organisme : NIH HHS
ID : R01GM136946.
Pays : United States
Organisme : NIH HHS
ID : R35NS122302
Pays : United States
Organisme : NIH HHS
ID : R35NS122302
Pays : United States
Organisme : NIH HHS
ID : R35NS122302
Pays : United States
Organisme : NIH HHS
ID : R01GM136946.
Pays : United States
Organisme : NIH HHS
ID : R35NS122302
Pays : United States
Organisme : NIH HHS
ID : R01NS097542-01
Pays : United States
Organisme : NIH HHS
ID : R35NS122302
Pays : United States
Informations de copyright
© 2024. The Author(s).
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