Phosphorylated and aggregated TDP-43 with seeding properties induced upon mutant Huntingtin polyglutamine expression in human cellular models

May 7, 2026

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Phosphorylated TDP-43 (pTDP-43) constitutes a major hallmark of ALS and FTLD–TDP, yet its involvement extends across multiple neurodegenerative proteinopathy contexts. In human cell culture, expression of mutant Huntingtin carrying 80–97 polyglutamine repeats drives aggregation and phosphorylation of endogenous TDP-43, while non-pathogenic Huntingtin with 25 repeats remains ineffective. Mutant Huntingtin aggregation occurs first, followed by pTDP-43 accumulation and co-localization at mHtt inclusions, mirroring observations in Huntington patient brains. Detergent-insoluble fractions containing mHtt–pTDP-43 co-aggregates act as seeds that promote further TDP-43 aggregation in cells. The prion protein PrPC reduces mutant Huntingtin aggregation in parallel with decreased TDP-43 aggregation and phosphorylation, reinforcing a tight mechanistic link between the two proteins.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages18

Reading Time45 min

AccessFree to download

May 7, 2026

Upload by Logic