Cholesterol restores cortico-striatal synaptic connectivity in Huntington's disease through BDNF-TrkB signalling, supporting a role for cholesterol pathways implicated by human genetic modifier studies.

Cortico-striatal synaptic dysfunction is an early hallmark of Huntington's disease (HD), yet the mechanisms underlying synapse loss and its reversibility remain poorly understood. Brain cholesterol is essential for neuronal and synaptic function, and dysregulated cholesterol metabolism has emerged as a key feature of HD, with reduced cholesterol biosynthesis reported in rodent models and cholesterol replenishment shown to be beneficial. Consistent with these findings, GWAS identified HD modifier loci outside canonical DNA repair pathways, including MED15, which among its functions supports SREBF2-mediated transcription of cholesterol biosynthesis genes, and a chr22 locus encompassing SREBF2, the master regulator of cholesterol biosynthesis. These findings suggest that pathways regulating cholesterol homeostasis may contribute to modifying the course of HD. Here, we show that increasing cholesterol availability prevents synapse loss and restores cortico-striatal connectivity in HD models. Cholesterol supplementation restores excitatory synapse density in vivo and in vitro. In primary HD neurons, cholesterol stabilizes dendritic spines and promotes the enrichment of GluA1-containing AMPA receptors in mature mushroom spines during chemically induced long-term potentiation, consistent with improved synaptic plasticity. Using microfluidic devices to spatially resolve the cortico-striatal circuit, we identified a compartment-specific mechanism whereby cholesterol delivery to cortical neurons is necessary and sufficient to restore cortico-striatal connectivity, whereas cholesterol administration to the striatal compartment selectively restores intra-striatal inhibitory synapses. Mechanistically, NMDA receptor and BDNF/TrkB signalling mediate the cholesterol-dependent restoration of synaptic connectivity, establishing cholesterol as a critical regulator of cortico-striatal synaptic integrity in HD and supporting targeting cholesterol homeostasis as a therapeutic strategy to restore synaptic function.