Lentiviral-mediated knock-down of GD3 synthase protects against MPTP-induced motor deficits and neurodegeneration.

Neurosci Lett 2019

Dhanushkodi A, Xue Y, Roguski EE

Abstract

  1. Neurosci Lett. 2019 Jan 23;692:53-63. doi: 10.1016/j.neulet.2018.10.038. Epub 2018 Nov 1.

Lentiviral-mediated knock-down of GD3 synthase protects against MPTP-induced motor deficits and neurodegeneration.

Dhanushkodi A(1), Xue Y(1), Roguski EE(2), Ding Y(3), Matta SG(2), Heck D(4), Fan GH(3), McDonald MP(5).

Author information: (1)Department of Neurology, University of Tennessee Health Science Center Memphis, TN 38163, United States. (2)Department of Pharmacology, University of Tennessee Health Science Center, Memphis, TN 38163, United States. (3)Department of Pharmacology & Toxicology, Virginia Commonwealth University, Richmond, VA 23284, United States. (4)Department of Anatomy & Neurobiology, University of Tennessee Health Science Center Memphis, TN 38163, United States. (5)Department of Neurology, University of Tennessee Health Science Center Memphis, TN 38163, United States; Department of Anatomy & Neurobiology, University of Tennessee Health Science Center Memphis, TN 38163, United States. Electronic address: mike@tennessee.edu.

Converging evidence demonstrates an important role for gangliosides in brain function and neurodegenerative diseases. Exogenous GM1 is broadly neuroprotective, including in rodent, feline, and primate models of Parkinson’s disease, and has shown positive effects in clinical trials. We and others have shown that inhibition of the ganglioside biosynthetic enzyme GD3 synthase (GD3S) increases endogenous levels GM1 ganglioside. We recently reported that targeted deletion of St8sia1, the gene that codes for GD3S, prevents motor impairments and significantly attenuates neurodegeneration induced by 1-methy-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The current study investigated the effects of GD3S inhibition on the neurotoxicity and parkinsonism induced by MPTP. Mice were injected intrastriatally with a lentiviral-vector-mediated shRNA construct targeting GD3S (shGD3S) or a scrambled-sequence control (scrRNA). An

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