title: Adeno-associated virus type 2 vector-mediated glial cell line-derived neurotrophic factor gene transfer induces neuroprotection and neuroregeneration in a ubiquitin-proteasome system impairment animal model of Parkinson's disease.
abstract: BACKGROUND
  The impairment of the ubiquitin-proteasome system (UPS) is a cellular mechanism underlying the neurodegenerative process in Parkinson's disease (PD). A mouse model induced by the selective proteasome inhibitor lactacystin targeting on substantia nigra has been demonstrated to be valuable in investigating etiopathogenesis and neuroprotection for PD.
  
  
  OBJECTIVE
  In the present study, we used adeno-associated virus type 2 vector (AAV2) encoding glial cell line-derived neurotrophic factor (GDNF) injected into the striatum of this animal model to test the effectiveness and possible mechanisms of GDNF gene therapy.
  
  
  RESULTS
  Our results showed that AAV2-mediated GDNF gene therapy significantly attenuated lactacystin-induced loss of nigral dopamine (DA) neurons and striatal DA levels. Furthermore, we found that GDNF protein is mostly expressed in astrocytes in the subventricular zone (SVZ) and dentate gyrus (DG). AAV2-mediated GDNF therapy can induce neurogenesis in the SVZ and DG, and increase the number of nigral newborn DA neurons.
  
  
  CONCLUSIONS
  These data indicate that AAV2-mediated GDNF gene therapy can protect the nigral DA neurons from the UPS impairment-induced degeneration, which may partly result from the nigral DA neuron regeneration in the brain, and such experimental results may have implications for the treatment of PD.
authors.affiliation: Institute of Neurology, Ruijin Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China.
authors.forename: Yunlan
authors.initials: Y
authors.lastname: Du
authors.forename: Xiaojie
authors.initials: X
authors.lastname: Zhang
authors.forename: Qingqing
authors.initials: Q
authors.lastname: Tao
authors.forename: Sheng
authors.initials: S
authors.lastname: Chen
authors.forename: Weidong
authors.initials: W
authors.lastname: Le
mesh_terms: D000818:Animals; D000229:Dependovirus / Q000235:genetics*; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000008:administration & dosage; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000008:administration & dosage* / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009416:Nerve Regeneration / Q000235:genetics*; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism / Q000517:prevention & control; D046988:Proteasome Endopeptidase Complex / Q000235:genetics* / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D025801:Ubiquitin / Q000235:genetics* / Q000378:metabolism; D054875:Ubiquitination / Q000235:genetics
chemical_list: D051100:Glial Cell Line-Derived Neurotrophic Factor; D018696:Neuroprotective Agents; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex