A LIPID‑TRANSFER PROTEIN AT THE CORE OF MOTOR DYSFUNCTION: VPS13A’S ROLE IN CORTICO‑STRIATAL CONNECTIVITY, SYNAPTIC PLASTICITY, AND THE BRAIN PROTEOME

Loss‑of‑function mutations in the lipid‑transfer protein VPS13A cause VPS13A disease (chorea‑acanthocytosis), an ultra‑rare autosomal recessive neurodegenerative disorder characterised by the selective degeneration of basal ganglia circuits, leading to adult‑onset chorea and dystonia. Yet the physiological role of VPS13A in neural circuits remains poorly understood. We assessed the role of VPS13A in motor function, striatal connectivity, cortico-striatal synaptic plasticity, and proteomic profile using a complete VPS13A knock-out (KO) mouse model. Thirty‑three‑week‑old VPS13A KO mice display reduced locomotor activity in the open field, increased descending time in the vertical pole and reduced motor learning on the accelerating rotarod compared with wild‑type littermates. Multimodal MRI indicates general striatal functional network deficits and reduced GABA levels in the striatum of KO mice. Moreover, electrophysiological ex vivo recordings reveal impaired long‑term depression in the dorsolateral striatum of KO mice. We also analyzed VPS13A‑KO–induced proteomic alterations in cortex and striatum, identifying 289 differentially expressed proteins in cortex and 116 in striatum. We found VPS13A-KO-induced downregulation of proteins involved in mitochondrial function; while, at the synaptic level, VPS13A-KO induced overexpression of proteins involved in neurotransmission and synaptic function. Our findings demonstrate that the lack of lipid-transfer protein VPS13A impairs motor learning and coordination, cortico-striatal connectivity, synaptic plasticity and proteome profiles. These results highlight the key role of intracellular lipid distribution in sustaining neural plasticity and functional networks, providing insight into why basal ganglia circuits are particularly vulnerable in motor disorders such as VPS13A disease.