The anti-leprosy drug clofazimine reduces polyQ toxicity through activation of PPARγ.

ABSTRACT:

Background

PolyQ diseases are autosomal dominant neurodegenerative disorders caused by the expansion of CAG repeats. While of slow progression, these diseases are ultimately fatal and lack effective therapies.

Methods

A high-throughput chemical screen was conducted to identify drugs that lower the toxicity of a protein containing the first exon of Huntington's disease (HD) protein huntingtin (HTT) harbouring 94 glutamines (Htt-Q₉₄). Candidate drugs were tested in a wide range of in vitro and in vivo models of polyQ toxicity.

Findings

The chemical screen identified the anti-leprosy drug clofazimine as a hit, which was subsequently validated in several in vitro models. Computational analyses of transcriptional signatures revealed that the effect of clofazimin

SUBMITTER: Li X 

PROVIDER: S-EPMC11088276 | biostudies-literature | 2024 May

REPOSITORIES: biostudies-literature