title: GDNF fails to exert neuroprotection in a rat α-synuclein model of Parkinson's disease.
abstract: The neuroprotective effect of the glial cell line-derived neurotrophic factor has been extensively studied in various toxic models of Parkinson's disease. However, it remains unclear whether this neurotrophic factor can protect against the toxicity induced by the aggregation-prone protein α-synuclein. Targeted overexpression of human wild-type α-synuclein in the nigrostriatal system, using adeno-associated viral vectors, causes a progressive degeneration of the nigral dopamine neurons and the development of axonal pathology in the striatum. In the present study, we investigated, using different paradigms of delivery, whether glial cell line-derived neurotrophic factor can protect against the neurodegenerative changes and the cellular stress induced by α-synuclein. We found that viral vector-mediated delivery of glial cell line-derived neurotrophic factor into substantia nigra and/or striatum, administered 2-3 weeks before α-synuclein, was inefficient in preventing the wild-type α-synuclein-induced loss of dopamine neurons and terminals. In addition, glial cell line-derived neurotrophic factor overexpression did not ameliorate the behavioural deficit in this rat model of Parkinson's disease. Quantification of striatal α-synuclein-positive aggregates revealed that glial cell line-derived neurotrophic factor had no effect on α-synuclein aggregation. These data provide the evidence for the lack of neuroprotective effect of glial cell line-derived neurotrophic factor against the toxicity of human wild-type α-synuclein in an in vivo model of Parkinson's disease. The difference in neuroprotective efficacy of glial cell line-derived neurotrophic factor seen in our model and the commonly used neurotoxin models of Parkinson's disease, raises important issues pertinent to the interpretation of the results obtained in preclinical models of Parkinson's disease, and their relevance for the therapeutic use glial cell line-derived neurotrophic factor in patients with Parkinson's disease.
authors.affiliation: Wallenberg Neuroscience Centre, Sölvegatan 17, 221 84 Lund, Sweden.
authors.forename: Mickael
authors.initials: M
authors.lastname: Decressac
authors.forename: Ayse
authors.initials: A
authors.lastname: Ulusoy
authors.forename: Bengt
authors.initials: B
authors.lastname: Mattsson
authors.forename: Biljana
authors.initials: B
authors.lastname: Georgievska
authors.forename: Marina
authors.initials: M
authors.lastname: Romero-Ramos
authors.forename: Deniz
authors.initials: D
authors.lastname: Kirik
authors.forename: Anders
authors.initials: A
authors.lastname: Björklund
mesh_terms: D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D030801:Animals, Genetically Modified; D002452:Cell Count; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D015259:Dopamine Agents / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D005822:Genetic Vectors / Q000502:physiology; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000008:administration & dosage* / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D007381:Intermediate Filament Proteins / Q000235:genetics / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000209:etiology / Q000517:prevention & control*; D010300:Parkinson Disease / Q000150:complications; D051381:Rats; D017207:Rats, Sprague-Dawley; D018709:Statistics, Nonparametric; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism; D050493:Vesicular Monoamine Transport Proteins / Q000378:metabolism
chemical_list: D015259:Dopamine Agents; D051100:Glial Cell Line-Derived Neurotrophic Factor; D007381:Intermediate Filament Proteins; C493454:Slc18a2 protein, rat; D050493:Vesicular Monoamine Transport Proteins; C430456:desmuslin; D049452:Green Fluorescent Proteins; D000661:Amphetamine