Structural and functional neuroprotection in a rat model of Huntington's disease by viral gene transfer of GDNF

Exp Neurol. 2003 Jun;181(2):213-23. doi: 10.1016/s0014-4886(03)00044-x.


Huntington's disease (HD) is an autosomal dominant disorder caused by an expanded polyglutamine (CAG) tract at the IT15 locus on chromosome 4. These excessive repeats lead to the degeneration of striatal and cortical neurons resulting in a devastating cognitive, psychiatric, and motor disorder for which no treatments are available. Neurotrophic factors support the viability of striatal neurons suggesting that they might prevent the inevitable neural degeneration and its accompanying functional decline associated with HD. The present study investigated whether glial cell line-derived neurotrophic factor (GDNF) delivered by an adeno associated virus could provide structural and functional neuroprotection in a rat model of HD. Lewis rats received bilateral injections of either AAV-GDNF (n = 12) or AAV-green fluorescence protein (AAV-GFP, n = 12) into the striatum followed 2 weeks later by chronic subcutaneous infusions of the mitochondrial toxin, 3-nitropropionic acid (3-NP, 38 mg/kg). All rats underwent 4 weeks of behavioral testing and were then sacrificed. Following 3-NP, the performance by AAV-GFP-treated rats on a raised platform motor task deteriorated while the performance by AAV-GDNF-treated rats was near normal (P < 0.001). AAV-GDNF-treated rats also received better scores on a blinded semi-quantitative neurological scale compared to rats receiving AAV-GFP (P < 0.001). Histological analyses supported our behavioral findings. 3-NP-treated rats receiving AAV-GDNF displayed 70% more NeuN-immunoreactive neurons compared to 3-NP-treated rats receiving AAV-GFP (P = 0.002). Similar findings were seen with dopamine-and-adenosine-3'5'-monophosphate-regulated phosphoprotein (DARPP-32) staining. These data indicate that the viral-mediated gene transfer of GDNF into the striatum provides neuroanatomical and behavioral protection in a rodent model of HD.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Behavior, Animal / drug effects
  • Corpus Striatum / drug effects
  • Corpus Striatum / metabolism
  • Corpus Striatum / pathology
  • Dependovirus / genetics*
  • Disease Models, Animal
  • Genetic Therapy / methods*
  • Glial Cell Line-Derived Neurotrophic Factor
  • Green Fluorescent Proteins
  • Huntington Disease / chemically induced
  • Huntington Disease / pathology
  • Huntington Disease / therapy*
  • Injections
  • Leukocyte Common Antigens / biosynthesis
  • Luminescent Proteins / biosynthesis
  • Luminescent Proteins / genetics
  • Male
  • Motor Activity / drug effects
  • Motor Activity / genetics
  • Nerve Growth Factors / administration & dosage*
  • Nerve Growth Factors / biosynthesis
  • Nerve Growth Factors / genetics
  • Neurologic Examination
  • Neuroprotective Agents / administration & dosage*
  • Neuroprotective Agents / metabolism
  • Nitro Compounds
  • Propionates
  • Rats
  • Rats, Inbred Lew
  • Severity of Illness Index
  • Stereotaxic Techniques
  • Treatment Outcome


  • Gdnf protein, rat
  • Glial Cell Line-Derived Neurotrophic Factor
  • Luminescent Proteins
  • Nerve Growth Factors
  • Neuroprotective Agents
  • Nitro Compounds
  • Propionates
  • Green Fluorescent Proteins
  • Leukocyte Common Antigens
  • 3-nitropropionic acid