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We have previously shown that modification of brain gangliosides by targeted deletion of GD3 synthase (GD3S) is neuroprotective in\u00a0vivo and in\u00a0vitro. 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\u2010mg\/kg 1\u2010methyl\u20104\u2010phenyl\u20101,2,3,6\u2010tetrahydropyridine (MPTP). C57BL\/6N wild\u2010type mice were assessed on a battery of sensorimotor tasks and a reaction\u2010time 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\u2010associated viral (AAV) vector expressing a short\u2010hairpin RNA (shRNA) construct targeting\n                    <jats:italic>St8sia1<\/jats:italic>\n                    , the gene that codes for GD3S, or a scrambled\u2010sequence control (scrRNA). After 4\u2009weeks, mice received MPTP or saline injections. MPTP\u2010lesioned 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\u2010emerged 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.\n                  <\/jats:p>","DOI":"10.1111\/ejn.70061","type":"journal-article","created":{"date-parts":[[2025,3,17]],"date-time":"2025-03-17T02:14:47Z","timestamp":1742177687000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Gene Therapy Targeting GD3 Synthase Protects Against MPTP\u2010Induced Parkinsonism and Executive Dysfunction"],"prefix":"10.1111","volume":"61","author":[{"given":"Panchanan","family":"Maiti","sequence":"first","affiliation":[{"name":"Department of Neurology University of Tennessee Health Science Center  Memphis Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Xue","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Tennessee Health Science Center  Memphis Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tonia\u00a0S.","family":"Rex","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology University of Tennessee Health Science Center  Memphis Tennessee USA"},{"name":"Department of Ophthalmology and Visual Sciences Vanderbilt University  Nashville Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9642-964X","authenticated-orcid":false,"given":"Michael\u00a0P.","family":"McDonald","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Tennessee Health Science Center  Memphis Tennessee USA"},{"name":"Department of Anatomy &amp; 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