Cell type-selective AADC expression reduces motor deficits and dyskinesia in Parkinson's disease mouse models

Abstract

Degeneration of midbrain dopamine (DA) neurons and the resulting loss of striatal dopamine signaling are hallmarks of Parkinsons disease (PD). Although the dopamine precursor levodopa (L-DOPA) provides symptomatic relief, prolonged treatment often leads to abnormal involuntary movements (dyskinesia). Previous adeno-associated virus (AAV) approaches delivering aromatic L-amino acid decarboxylase (AADC) to the striatum under a ubiquitous promoter enhanced local dopamine synthesis and improved PD motor deficits, but this broad targeting strategy limited insight into the cellular populations underlying the behavioral improvements. Here, we engineered enhancer-driven AAVs to direct AADC expression to defined striatal and midbrain cell populations and paired these regulatory elements with a blood-brain barrier-penetrant capsid to enable both systemic and direct delivery. Targeted expression restored motor performance at reduced L-DOPA doses and decreased dyskinesia-like behaviors, producing improvements comparable to or greater than those achieved with ubiquitous expression. Distinct neuronal and non-neuronal populations each supported motor rescue but improved different behavioral domains to different extents, indicating complementary cell type-specific roles within PD-relevant circuits. Together, these findings establish enhancer-driven, cell type-specific AADC delivery as a better-tolerated strategy that enables rescue of motor deficits at lower L-DOPA doses in PD models.