Language

English

Publication Date

5-1-2025

Journal

Molecular Systems Biology

DOI

10.1038/s44320-025-00096-3

PMID

40169779

PMCID

PMC12048488

PubMedCentral® Posted Date

4-1-2025

PubMedCentral® Full Text Version

Post-print

Abstract

Huntington's disease (HD) is a debilitating neurodegenerative disorder affecting an individual's cognitive and motor abilities. HD is caused by a mutation in the huntingtin gene producing a toxic polyglutamine-expanded protein (mHTT) and leading to degeneration in the striatum and cortex. Yet, the molecular signatures that underlie tissue-specific vulnerabilities remain unclear. Here, we investigate this aspect by leveraging multi-epitope protein interaction assays, subcellular fractionation, thermal proteome profiling, and genetic modifier assays. The use of human cell, mouse, and fly models afforded capture of distinct subcellular pools of epitope-enriched and tissue-dependent interactions linked to dysregulated cellular pathways and disease relevance. We established an HTT association with nearly all subunits of the transcriptional regulatory Mediator complex (20/26), with preferential enrichment of MED15 in the tail domain. Using HD and KO models, we find HTT modulates the subcellular localization and assembly of the Mediator. We demonstrated striatal enriched and functional interactions with regulators of calcium homeostasis and chromatin remodeling, whose disease relevance was supported by HD fly genetic modifiers assays. Altogether, we offer insights into tissue- and localization-dependent (m)HTT functions and pathobiology.

Keywords

Huntingtin Protein, Animals, Humans, Huntington Disease, Mice, Corpus Striatum, Epitopes, Disease Models, Animal, Drosophila melanogaster, HEK293 Cells

Published Open-Access

yes

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