Gene Therapy Targeting GD3 Synthase Protects Against MPTP-Induced Parkinsonism and Executive Dysfunction

Abstract

More than half of Parkinson's patients exhibit fronto-striatally mediated executive dysfunction, including deficits in sustained attention, judgment, and impulse control. We have previously shown that modification of brain gangliosides by targeted deletion of GD3 synthase (GD3S) is neuroprotective in vivo and in vitro. The objective of the present study was to determine whether GD3S knockdown will protect neurons and prevent executive dysfunction following a subchronic regimen of 25-mg/kg 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). C57BL/6N wild-type mice were assessed on a battery of sensorimotor tasks and a reaction-time task that included measures of sustained attention and impulse control. Sustained attention was measured by response accuracy and reaction time; impulsivity was measured by premature responding in the response holes or the food well during the precue period. After reaching stable performance, mice received intrastriatal injections of a recombinant adeno-associated viral (AAV) vector expressing a short-hairpin RNA (shRNA) construct targeting St8sia1, the gene that codes for GD3S, or a scrambled-sequence control (scrRNA). After 4 weeks, mice received MPTP or saline injections. MPTP-lesioned mice in the scrRNA control group exhibited loss of impulse control in the sessions following MPTP injections, compared to the other three groups. These deficits abated with extended training but re-emerged on challenge sessions with shorter cue durations or longer precue durations. GD3S knockdown partially protected nigrostriatal neurons from MPTP neurotoxicity and prevented the motor impairments (coordination, bradykinesia, fine motor skills) and loss of impulse control. Our data suggest that inhibition of GD3S warrants further investigation as a novel therapeutic strategy for Parkinson's disease.