Hyun Jin Jung (KBRI)

Youngshik Choe (KBRI)

Hyun Jin Jung (KBRI)

Seungeun Yeo (KBRI)

Youngshik Choe (KBRI)

Huntington’s disease (HD) is a progressive neurodegenerative disorder marked by neuronal degeneration and the accumulation of intracellular inclusions containing mutant huntingtin (mHTT) protein. The disaggregation of misfolded, aggregation-prone proteins is essential for sustaining neuronal integrity. In this study, we investigated the molecular pathways governing the segregation of intracellular protein aggregates enriched with polyglutamine (polyQ) expansions within huntingtin proteins. A naturally derived bioactive compound demonstrated the capacity to limit the formation and propagation of aggregation foci. To elucidate the underlying proteostatic mechanisms, we performed an interactome analysis of the protein aggregates, which revealed that aggresome-associated chaperones, including Hsc70, operate downstream of aggregate segregation. Treatment with the compound promoted proteomic homeostasis in neuronal cells, in part by remodeling pathways linked to extracellular vesicle release. These findings suggest that modulation of the proteome and protein quality control machinery by certain bioactive agents may contribute to alleviating proteopathic burden in post-mitotic neurons.

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