REGION-SPECIFIC TRANSCRIPTIONAL PROGRAMS UNDERLYING DOPAMINE HYPERSENSITIVITY IN VMAT2 DEFICIENCY

Parkinson’s disease and related parkinsonian disorders are commonly attributed to dopaminergic dysfunction; however, alterations in dopamine handling can trigger compensatory cellular and network adaptations that remain incompletely understood. Parkinsonism–Dystonia Type 2 (PKDYS2) is a rare neurodevelopmental disorder caused by biallelic mutations in SLC18A2, encoding the vesicular monoamine transporter 2 (VMAT2), and is characterized by early-onset parkinsonism, dystonia, and atypical responses to dopaminergic manipulation. To investigate the molecular consequences of impaired vesicular monoamine storage, we combined long-term clinical phenotyping of 12 individuals with PKDYS2 with the generation of a knock-in mouse model carrying a pathogenic Slc18a2 variant identified in patients. VMAT2-deficient mice exhibited progressive motor abnormalities, including dystonia, reduced spontaneous locomotion, and impaired coordination, recapitulating key aspects of the human phenotype. Bulk RNA sequencing of the striatum and prefrontal cortex revealed pronounced region-specific transcriptional changes, implicating altered dopaminergic signaling, synaptic plasticity, inflammatory pathways, and activity-dependent gene regulation. These transcriptional signatures are consistent with a state of functional dopamine deficiency accompanied by postsynaptic and circuit-level adaptation rather than simple neurotransmitter loss. In parallel, clinical observations demonstrated that dopaminergic perturbation can unmask maladaptive responses, supporting the relevance of transcriptional remodeling identified in the mouse model. Together, these data define molecular and regional gene-expression changes associated with chronic VMAT2 dysfunction and provide a resource for exploring mechanisms of dopamine hypersensitivity, synaptic adaptation, and network instability relevant to both rare monogenic parkinsonism and broader dopaminergic disorders.