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

Proc Natl Acad Sci U S A. 2006 Jun 13;103(24):9345-50. doi: 10.1073/pnas.0508875103. Epub 2006 Jun 2.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal / physiology
  • Cell Death
  • Corpus Striatum / cytology
  • Corpus Striatum / metabolism
  • Dependovirus / genetics
  • Dependovirus / metabolism
  • Disease Models, Animal
  • Female
  • Gene Transfer Techniques*
  • Genetic Therapy
  • Glial Cell Line-Derived Neurotrophic Factor Receptors / metabolism
  • Glial Cell Line-Derived Neurotrophic Factors / genetics
  • Glial Cell Line-Derived Neurotrophic Factors / metabolism*
  • Glial Cell Line-Derived Neurotrophic Factors / therapeutic use
  • Humans
  • Huntingtin Protein
  • Huntington Disease / genetics
  • Huntington Disease / pathology*
  • Huntington Disease / physiopathology*
  • Huntington Disease / therapy
  • Inclusion Bodies / chemistry
  • Male
  • Mice
  • Mice, Transgenic
  • Nerve Tissue Proteins / metabolism
  • Neurons / cytology
  • Neurons / metabolism
  • Neuroprotective Agents / metabolism*
  • Neuroprotective Agents / therapeutic use
  • Nuclear Proteins / metabolism
  • Rats


  • Glial Cell Line-Derived Neurotrophic Factor Receptors
  • Glial Cell Line-Derived Neurotrophic Factors
  • Htt protein, mouse
  • Huntingtin Protein
  • Nerve Tissue Proteins
  • Neuroprotective Agents
  • Nuclear Proteins