FUNCTIONAL IMPAIRMENT AND PROTEIN INTERACTION PROFILE OF THE LIPID TRANSFER PROTEIN VPS13A IN THE MOUSE BRAIN

VPS13A disease (Chorea-Acanthocytosis, ChAc) is caused by loss-of-function mutations in the gene encoding the lipid-transfer protein VPS13A and is neuropathologically characterized by selective degeneration of the caudate nucleus and putamen, leading to adult-onset chorea and dystonia. In this study, we investigated the functional and neuropathological consequences of VPS13A loss using a complete VPS13A knock-out (KO) mouse model and analyzed the protein interaction profile of VPS13A in the cerebral cortex. Corticostriatal-dependent motor function was evaluated in 33-week-old VPS13A-KO mice using open field (OF) and accelerating rotarod (ARR) tests. VPS13A-KO mice showed reduced locomotor activity in the OF and impaired motor learning in the ARR, with sex-dependent differences. Histological analyses assessing neuronal density, astrogliosis and microgliosis revealed no significant differences between wildtype and VPS13A-KO mice at this age. To explore potential molecular mechanisms underlying the observed motor deficits, we analyzed the VPS13A interactome by immunoprecipitation from wild-type mouse cerebral cortex followed by mass spectrometry. We found that VPS13A interact predominantly with Mre11, Rad50 and Nbn, components of the MRN complex involved in DNA double-strand break repair and linked to mitochondrial genome maintenance. Understanding the protein interacting partners can provide novel insights toward the knowledge of ChAc pathophysiology. Together, these findings indicate that VPS13A deficiency leads to early motor learning impairments in the absence of overt neuropathological alterations and suggest that VPS13A may contribute to motor circuit function through pathways related to mitochondrial DNA repair. Ongoing studies aim to determine the impact of VPS13A loss on MRN complex function and mitochondrial DNA integrity.