Evaluation of curcumin as an exploratory pharmacological tool for modulating dysregulated molecular pathways in cellular models of Huntington's disease.

BACKGROUND: Huntington's disease (HD) is a monogenic neurodegenerative disorder caused by expansion of CAG trinucleotide repeats in the HTT gene, resulting in an aggregation-prone mutant huntingtin protein (mHTT) and progressive neuronal dysfunction. HD pathogenesis involves disturbances in protein homeostasis, mitochondrial function, oxidative stress, epigenetic regulation, and inflammatory signalling. We investigated the effects of curcumin, a naturally occurring polyphenol, on these disease-relevant processes in vitro. METHODS AND RESULTS: Using established HD cellular models, we examined the effects of curcumin on mHTT aggregation, mitochondrial function, oxidative stress, and endoplasmic reticulum stress. Curcumin reduced mHTT aggregation and PERK-eIF2α signalling in HD cells by elevating autophagic clearance. Curcumin treatment increased ATP levels, partially restored Ppargc1α and Nrf1 expression, reduced mitochondrial as well as cytosolic reactive oxygen species and H3K27 trimethylation. In HD patient-derived lymphoblastoid cell lines, curcumin treatment abrogated inflammatory responses. CONCLUSIONS: Curcumin alters multiple disease-relevant cellular processes in HD models, providing mechanistic insight into pathways associated with mHTT toxicity.