Viral delivery of glial cell line-derived neurotrophic factor improves behavior and protects striatal neurons in a mouse model of Huntington's disease

Jodi L. McBride, Shilpa Ramaswamy, Mehdi Gasmi, Raymond T. Bartus, Christopher D. Herzog, Eugene P. Brandon, Lili Zhou, Mark R. Pitzer, Elizabeth M. Berry-Kravis, Jeffrey H. Kordower

    Research output: Contribution to journalArticlepeer-review

    85 Scopus citations

    Abstract

    Huntington's disease (HD) is a fatal, genetic, neurological disorder resulting from a trinucleotide repeat expansion in the gene that encodes for the protein huntingtin. These excessive repeats confer a toxic gain of function on huntingtin, which leads to the degeneration of striatal and cortical neurons and a devastating motor, cognitive, and psychological disorder. Trophic factor administration has emerged as a compelling potential therapy for a variety of neurodegenerative disorders, including HD. We previously demonstrated that viral delivery of glial cell line-derived neurotrophic factor (GDNF) provides structural and functional neuroprotection in a rat neurotoxin model of HD. In this report we demonstrate that viral delivery of GDNF into the striatum of presymptomatic mice ameliorates behavioral deficits on the accelerating rotorod and hind limb clasping tests in transgenic HD mice. Behavioral neuroprotection was associated with anatomical preservation of the number and size of striatal neurons from cell death and cell atrophy. Additionally, GDNF-treated mice had a lower percentage of neurons containing mutant huntingtin-stained inclusion bodies, a hallmark of HD pathology. These data further support the concept that viral vector delivery of GDNF may be a viable treatment for patients suffering from HD.

    Original languageEnglish (US)
    Pages (from-to)9345-9350
    Number of pages6
    JournalProceedings of the National Academy of Sciences of the United States of America
    Volume103
    Issue number24
    DOIs
    StatePublished - Jun 13 2006

    Keywords

    • Adenoassociated virus
    • Gene therapy
    • Neurodegeneration
    • Neuroprotection
    • Polyglutamine

    ASJC Scopus subject areas

    • General

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