Anterograde axonal transport of AAV2-GDNF in rat basal ganglia

Mol Ther. 2011 May;19(5):922-7. doi: 10.1038/mt.2010.248. Epub 2010 Nov 23.

Abstract

We elucidated the effects of parkinsonian degeneration on trafficking of AAV2-GDNF in the nigro-striatum (nigro-ST) of unilaterally 6-hydroxydopamine (6-OHDA)-lesioned rats. Vector infused into striatum (ST) was transported to substantia nigra (SN), both pars compacta (SNc), and pars reticulata (SNr). In the lesioned hemisphere, glial cell line-derived neurotrophic factor (GDNF) immunoreactivity was only found in SNr consistent with elimination of SNc dopaminergic (DA) neurons by 6-OHDA. Further analysis showed that striatal delivery of AAV2-GDNF resulted in GDNF expression in globus pallidus (GP), entopeduncular nucleus (EPN), and subthalamic nucleus (STN) in both lesioned and unlesioned hemispheres. Injection of vector into SN, covering both SNc and SNr, resulted in striatal expression of GDNF in the unlesioned hemisphere but not in the lesioned hemisphere. No expression was seen in GP or EPN. We conclude that adeno-associated virus serotype 2 (AAV2) is transported throughout the nigro-ST exclusively by anterograde transport. This transport phenomenon directs GDNF expression throughout the basal ganglia in regions that are adversely affected in Parkinson's disease (PD) in addition to SNc. Delivery of vector to SN, however, does not direct expression of GDNF in ST, EPN, or GP. On this basis, we believe that striatal delivery of AAV2-GDNF is the preferred course of action for trophic rescue of DA function.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Axonal Transport* / drug effects
  • Basal Ganglia / metabolism*
  • Dependovirus / genetics*
  • Entopeduncular Nucleus / cytology
  • Gene Expression
  • Genetic Therapy / methods
  • Glial Cell Line-Derived Neurotrophic Factor / genetics
  • Glial Cell Line-Derived Neurotrophic Factor / metabolism*
  • Globus Pallidus / cytology
  • Male
  • Nerve Growth Factors / metabolism
  • Oxidopamine / pharmacology
  • Parkinson Disease / metabolism
  • Parkinson Disease / pathology
  • Parkinson Disease / therapy
  • Rats
  • Rats, Sprague-Dawley
  • Substantia Nigra / metabolism
  • Substantia Nigra / pathology
  • Subthalamic Nucleus / cytology

Substances

  • Glial Cell Line-Derived Neurotrophic Factor
  • Nerve Growth Factors
  • Oxidopamine