Pathogenic mutations in UBQLN2 exhibit diverse aggregation propensity and neurotoxicity

Nathaniel Safren, Thuy P. Dao, Harihar Milaganur Mohan, Camellia Huang, Bryce Trotter, Carlos A. Castañeda, Henry Paulson, Sami Barmada, Lisa M. Sharkey

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Article number6049
JournalScientific reports
Volume14
Issue number1
DOIs
StatePublished - Dec 2024

ASJC Scopus subject areas

  • General

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