INTRODUCTION: Protein quality control (PQC) is a vital cellular system often impaired in neurodegenerative diseases such as Huntington’s disease (HD). Valosin-containing protein (VCP/p97) is a central PQC regulator and its activity is shaped by cofactors that guide its function. HD is caused by polyglutamine expansion in the huntingtin (HTT) protein, leading to toxic aggregation and selective loss of medium spiny neurons (MSNs). While mutant HTT toxicity is well described, the role of VCP/p97 regulation in disease progression remains unclear.

AIM(S): We aim to determine how a selected VCP/p97 cofactor – small VCP-interacting protein (SVIP), identified from HD omics data, influences disease-relevant phenotypes.

METHOD(S): In the study we used a human model of HD based on direct conversion of patient fibroblasts into medium spiny neurons (miR-HD-MSNs), that by omitting the pluripotency stage preserves aging signatures of donor cells.

RESULTS: In miR-HD-MSNs, we assessed the expression level of SVIP and examined the effect of its manipulation on disease-relevant phenotypes, including HTT protein accumulation and cell survival. Preliminary data suggest that SVIP is enriched in neurons and that modulating its expression in HD-MSNs alters autophagic flux, potentially contributing to its functional effects.

CONCLUSIONS: Our study provides initial evidence that the VCP/p97 cofactor SVIP plays a modulatory role in Huntington’s disease pathology. Its enriched expression in neurons and impact on autophagic flux suggest that SVIP contributes to the regulation of proteostasis in HD-affected neurons. These findings support further investigation into SVIP as a candidate for targeting PQC dysfunction in Huntington’s disease.

FINANCIAL SUPPORT: The project is financed from the Sonata Bis 11 Grant (2021/42/E/NZ3/00439) – National Science Centre Poland.