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Disease-modifying effects of ganglioside GM1 in Huntington's disease models.

Authors
  • Alpaugh, Melanie1, 2
  • Galleguillos, Danny1, 2
  • Forero, Juan2, 3
  • Morales, Luis Carlos1
  • Lackey, Sebastian W1
  • Kar, Preeti1
  • Di Pardo, Alba1
  • Holt, Andrew1
  • Kerr, Bradley J2, 4
  • Todd, Kathryn G2, 5
  • Baker, Glen B2, 5
  • Fouad, Karim2, 3
  • Sipione, Simonetta6, 2
  • 1 Department of Pharmacology, University of Alberta, Edmonton, AB, Canada. , (Canada)
  • 2 Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB, Canada. , (Canada)
  • 3 Faculty of Rehabilitation Medicine, University of Alberta, Edmonton, AB, Canada. , (Canada)
  • 4 Department of Anesthesiology and Pain Medicine, University of Alberta, Edmonton, AB, Canada. , (Canada)
  • 5 Department of Psychiatry, University of Alberta, Edmonton, AB, Canada. , (Canada)
  • 6 Department of Pharmacology, University of Alberta, Edmonton, AB, Canada [email protected] , (Canada)
Type
Published Article
Journal
EMBO Molecular Medicine
Publisher
EMBO
Publication Date
Nov 01, 2017
Volume
9
Issue
11
Pages
1537–1557
Identifiers
DOI: 10.15252/emmm.201707763
PMID: 28993428
Source
Medline
Keywords
License
Unknown

Abstract

Huntington's disease (HD) is a progressive neurodegenerative disorder characterized by motor, cognitive and psychiatric problems. Previous studies indicated that levels of brain gangliosides are lower than normal in HD models and that administration of exogenous ganglioside GM1 corrects motor dysfunction in the YAC128 mouse model of HD In this study, we provide evidence that intraventricular administration of GM1 has profound disease-modifying effects across HD mouse models with different genetic background. GM1 administration results in decreased levels of mutant huntingtin, the protein that causes HD, and in a wide array of beneficial effects that include changes in levels of DARPP32, ferritin, Iba1 and GFAP, modulation of dopamine and serotonin metabolism, and restoration of normal levels of glutamate, GABA, L-Ser and D-Ser. Treatment with GM1 slows down neurodegeneration, white matter atrophy and body weight loss in R6/2 mice. Motor functions are significantly improved in R6/2 mice and restored to normal in Q140 mice, including gait abnormalities that are often resistant to treatments. Psychiatric-like and cognitive dysfunctions are also ameliorated by GM1 administration in Q140 and YAC128 mice. The widespread benefits of GM1 administration, at molecular, cellular and behavioural levels, indicate that this ganglioside has strong therapeutic and disease-modifying potential in HD.

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