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

Anandh Dhanushkodi, Yi Xue, Emily E. Roguski, Yun Ding, Shannon G. Matta, Detlef Heck, Guo Huang Fan, Michael Mcdonald

Research output: Contribution to journalArticle

Abstract

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 MPTP regimen of 18 mg/kg x 5 days reduced tyrosine-hydroxylase-positive neurons in the substantia nigra pars compacta of scrRNA-treated mice by nearly two-thirds. In mice treated with shGD3S the MPTP-induced lesion was approximately half that size. MPTP induced bradykinesia and deficits in fine motor skills in mice treated with scrRNA. These deficits were absent in shGD3S-treated mice. These results suggest that inhibition of GD3S protects against the nigrostriatal damage, bradykinesia, and fine-motor-skill deficits associated with MPTP administration.

LanguageEnglish (US)
Pages53-63
Number of pages11
JournalNeuroscience Letters
Volume692
DOIs
StatePublished - Jan 23 2019

Fingerprint

Hypokinesia
Motor Skills
Gangliosides
G(M1) Ganglioside
Felidae
Gene Deletion
Tyrosine 3-Monooxygenase
Parkinsonian Disorders
Brain Diseases
Neurodegenerative Diseases
Primates
Small Interfering RNA
Parkinson Disease
4-phenyl-1,2,3,6-tetrahydropyridine
Rodentia
Clinical Trials
Neurons
Enzymes
Inhibition (Psychology)
Pars Compacta

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

Cite this

Lentiviral-mediated knock-down of GD3 synthase protects against MPTP-induced motor deficits and neurodegeneration. / Dhanushkodi, Anandh; Xue, Yi; Roguski, Emily E.; Ding, Yun; Matta, Shannon G.; Heck, Detlef; Fan, Guo Huang; Mcdonald, Michael.

In: Neuroscience Letters, Vol. 692, 23.01.2019, p. 53-63.

Research output: Contribution to journalArticle

Dhanushkodi, Anandh ; Xue, Yi ; Roguski, Emily E. ; Ding, Yun ; Matta, Shannon G. ; Heck, Detlef ; Fan, Guo Huang ; Mcdonald, Michael. / Lentiviral-mediated knock-down of GD3 synthase protects against MPTP-induced motor deficits and neurodegeneration. In: Neuroscience Letters. 2019 ; Vol. 692. pp. 53-63.
@article{4c3bc40ed3dc450f96fb8a599f95dd6c,
title = "Lentiviral-mediated knock-down of GD3 synthase protects against MPTP-induced motor deficits and neurodegeneration",
abstract = "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 MPTP regimen of 18 mg/kg x 5 days reduced tyrosine-hydroxylase-positive neurons in the substantia nigra pars compacta of scrRNA-treated mice by nearly two-thirds. In mice treated with shGD3S the MPTP-induced lesion was approximately half that size. MPTP induced bradykinesia and deficits in fine motor skills in mice treated with scrRNA. These deficits were absent in shGD3S-treated mice. These results suggest that inhibition of GD3S protects against the nigrostriatal damage, bradykinesia, and fine-motor-skill deficits associated with MPTP administration.",
author = "Anandh Dhanushkodi and Yi Xue and Roguski, {Emily E.} and Yun Ding and Matta, {Shannon G.} and Detlef Heck and Fan, {Guo Huang} and Michael Mcdonald",
year = "2019",
month = "1",
day = "23",
doi = "10.1016/j.neulet.2018.10.038",
language = "English (US)",
volume = "692",
pages = "53--63",
journal = "Neuroscience Letters",
issn = "0304-3940",
publisher = "Elsevier Ireland Ltd",

}

TY - JOUR

T1 - Lentiviral-mediated knock-down of GD3 synthase protects against MPTP-induced motor deficits and neurodegeneration

AU - Dhanushkodi, Anandh

AU - Xue, Yi

AU - Roguski, Emily E.

AU - Ding, Yun

AU - Matta, Shannon G.

AU - Heck, Detlef

AU - Fan, Guo Huang

AU - Mcdonald, Michael

PY - 2019/1/23

Y1 - 2019/1/23

N2 - 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 MPTP regimen of 18 mg/kg x 5 days reduced tyrosine-hydroxylase-positive neurons in the substantia nigra pars compacta of scrRNA-treated mice by nearly two-thirds. In mice treated with shGD3S the MPTP-induced lesion was approximately half that size. MPTP induced bradykinesia and deficits in fine motor skills in mice treated with scrRNA. These deficits were absent in shGD3S-treated mice. These results suggest that inhibition of GD3S protects against the nigrostriatal damage, bradykinesia, and fine-motor-skill deficits associated with MPTP administration.

AB - 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 MPTP regimen of 18 mg/kg x 5 days reduced tyrosine-hydroxylase-positive neurons in the substantia nigra pars compacta of scrRNA-treated mice by nearly two-thirds. In mice treated with shGD3S the MPTP-induced lesion was approximately half that size. MPTP induced bradykinesia and deficits in fine motor skills in mice treated with scrRNA. These deficits were absent in shGD3S-treated mice. These results suggest that inhibition of GD3S protects against the nigrostriatal damage, bradykinesia, and fine-motor-skill deficits associated with MPTP administration.

UR - http://www.scopus.com/inward/record.url?scp=85056160876&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85056160876&partnerID=8YFLogxK

U2 - 10.1016/j.neulet.2018.10.038

DO - 10.1016/j.neulet.2018.10.038

M3 - Article

VL - 692

SP - 53

EP - 63

JO - Neuroscience Letters

T2 - Neuroscience Letters

JF - Neuroscience Letters

SN - 0304-3940

ER -