title: Targeted deletion of GD3 synthase protects against MPTP-induced neurodegeneration.
abstract: Parkinson's disease is a debilitating neurodegenerative condition for which there is no cure. Converging evidence implicates gangliosides in the pathogenesis of several neurodegenerative diseases, suggesting a potential new class of therapeutic targets. We have shown that interventions that simultaneously increase the neuroprotective GM1 ganglioside and decrease the pro-apoptotic GD3 ganglioside - such as inhibition of GD3 synthase (GD3S) or administration of sialidase - are neuroprotective in vitro and in a number of preclinical models. In this study, we investigated the effects of GD3S deletion on parkinsonism induced by 1-methyl-4phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPTP was administered to GD3S-/- mice or controls using a subchronic regimen consisting of three series of low-dose injections (11 mg/kg/day × 5 days each, 3 weeks apart), and motor function was assessed after each. The typical battery of tests used to assess parkinsonism failed to detect deficits in MPTP-treated mice. More sensitive measures - such as the force-plate actimeter and treadmill gait parameters - detected subtle effects of MPTP, some of which were absent in mice lacking GD3S. In wild-type mice, MPTP destroyed 53% of the tyrosine-hydroxylase (TH)-positive neurons in the substantia nigra pars compacta (SNc) and reduced striatal dopamine 60.7%. In contrast, lesion size was only 22.5% in GD3S-/- mice and striatal dopamine was reduced by 37.2%. Stereological counts of Nissl-positive SNc neurons that did not express TH suggest that neuroprotection was complete but TH expression was suppressed in some cells. These results show that inhibition of GD3S has neuroprotective properties in the MPTP model and may warrant further investigation as a therapeutic target.
authors.affiliation: Department of Comparative Medicine, University of Tennessee Health Science Center, Memphis, TN, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Akkhawattanangkul
authors.affiliation: Department of Neurology, University of Tennessee Health Science Center, Memphis, TN, USA.
authors.forename: P
authors.initials: P
authors.lastname: Maiti
authors.affiliation: Department of Neurology, University of Tennessee Health Science Center, Memphis, TN, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Xue
authors.affiliation: Department of Psychiatry & Behavioral Sciences, Duke University Medical Center, Durham, NC, USA.|Department of Cell Biology, Duke University Medical Center, Durham, NC, USA.|Department of Neurobiology, Duke University Medical Center, Durham, NC, USA.
authors.forename: D
authors.initials: D
authors.lastname: Aryal
authors.affiliation: Department of Psychiatry & Behavioral Sciences, Duke University Medical Center, Durham, NC, USA.|Department of Cell Biology, Duke University Medical Center, Durham, NC, USA.|Department of Neurobiology, Duke University Medical Center, Durham, NC, USA.
authors.forename: W C
authors.initials: WC
authors.lastname: Wetsel
authors.affiliation: Department of Comparative Medicine, University of Tennessee Health Science Center, Memphis, TN, USA.
authors.forename: D
authors.initials: D
authors.lastname: Hamilton
authors.affiliation: Department of Pharmacology & Toxicology, University of Kansas, Lawrence, KS, USA.
authors.forename: S C
authors.initials: SC
authors.lastname: Fowler
authors.affiliation: Department of Neurology, University of Tennessee Health Science Center, Memphis, TN, USA.|Department of Anatomy & Neurobiology, University of Tennessee Health Science Center, Memphis, TN, USA.
authors.forename: M P
authors.identifier: 0000-0002-9642-964X
authors.initials: MP
authors.lastname: McDonald
mesh_terms: D000818:Animals; D004298:Dopamine / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000378:metabolism / Q000473:pathology; D017353:Gene Deletion; D008124:Locomotion; D020267:MPTP Poisoning / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D012799:Sialyltransferases / Q000235:genetics*; D013378:Substantia Nigra / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology
chemical_list: D012799:Sialyltransferases; C043662:alpha-N-acetylneuraminate alpha-2,8-sialyltransferase; D004298:Dopamine
keywords: Bradykinesia; MPTP; Parkinson's disease; dopamine; gangliosides; motor function; neuroprotection; substantia nigra