A022 Karyopherin subunit beta 1 modulates polyglutamine-expanded huntingtin levels and fragmentation in cell models of Huntington’s disease

<h3>Background</h3> Nucleocytoplasmic transport proteins execute vital cellular functions and may play a crucial role in the molecular pathogenesis of Huntington’s disease (HD). Previous research on Machado-Joseph disease (MJD), another polyglutamine (polyQ) disease, showed that the transport protein karyopherin subunit beta 1 (KPNB1) triggers the degradation of the disease protein ataxin-3 (Atx3) via the mitochondrial caseinolytic peptidase proteolytic subunit (CLPP), attenuating the molecular pathogenesis. Interestingly, KPNB1 also directly interacts with the huntingtin (HTT) protein in a nuclear transport-related context. <h3>Aims</h3> We investigated whether KPNB1 exerts similar effects on the HD protein by modulating polyQ-expanded HTT protein and aggregate levels. <h3>Methods</h3> Cell lines overexpressing full-length or exon-1 HTT were used to analyse the effects of genetic or pharmacologic KPNB1 modulation. HTT full-length and fragment levels were examined via western blotting, while protein aggregation was assessed using filter retardation assays. Nucleocytoplasmic fractionations were performed to determine HTT subcellular localization following KPNB1 modulation. <h3>Results</h3> KPNB1 overexpression did not alter HTT localization but increased disease protein fragment levels. Unlike previous findings for Atx3 in MJD models, this fragmentation was not linked to CLPP activity, and polyQ-expanded HTT showed increased aggregation. Notably, these effects were absent in cells transfected with exon-1 HTT. <h3>Conclusions</h3> KPNB1 modulates HTT fragmentation and aggregation in a manner distinct from its effects on Atx3 in MJD. Further research is needed, but targeting KPNB1 could represent a potential therapeutic approach.