Iloperidone treatment mitigates the juvenile Huntington's disease phenotype possibly via Sigma‐1 receptor modulation

Juvenile Huntington's disease (jHD) is a severe genetic disorder with combined neurodegenerative and neurodevelopmental features, characterized by early onset and markedly reduced life expectancy. Despite extensive efforts, drug development has been largely unsuccessful and no effective therapy capable of mitigating the pathological phenotype is currently available. Here, we investigated the potential of the FDA-approved drug iloperidone to ameliorate disease-related phenotypes in cortical neurons differentiated from patient-derived induced pluripotent stem cells. Given previous reports indicating that iloperidone can bind the Sigma 1 Receptor (S1R), we hypothesized that activation of S1R-dependent proteostasis pathways could contribute to its potential therapeutic effects. Treatment with iloperidone in this human-relevant model led to enhanced clearance of protein aggregates, improved neuronal survival, and activation of an adaptive unfolded protein response, consistent with engagement of proteostasis mechanisms. To test the hypothesis of S1R involvement and clarify the underlying molecular mechanisms, we combined cellular experiments with molecular dynamics simulations of S1R in its apo and ligand-bound states and in vitro mass photometry experiments comparing iloperidone with PD144418, a well-established antagonist. The simulations revealed distinct receptor conformations depending on the bound ligand: iloperidone induced specific conformational changes, whereas PD144418 behaved similarly to the apo receptor. Consistently, the two ligands exerted opposite effects on S1R oligomerization in vitro. Overall, the integration of experimental and computational data supports a model in which iloperidone behaves as an S1R agonist, promoting receptor dissociation and phenotypic recovery through modulation of proteostasis.