Lentiviral nigral delivery of GDNF does not prevent neurodegeneration in a genetic rat model of Parkinson's disease

• Published in: Neurobiology of disease 2004-11, Vol.17 (2), p.283-289
• Main Authors: Lo Bianco, C., Déglon, N., Pralong, W., Aebischer, P.
• Format: Article
• Language: English
• Subjects: alpha-Synuclein; Animals; Dopaminergic neurons; Female; Gene therapy; Gene Transfer Techniques; Genetic model; Genetic Vectors; Glial Cell Line-Derived Neurotrophic Factor; Humans; Immunohistochemistry; Lentiviral vector; Lentivirus - genetics; Nerve Degeneration - etiology; Nerve Degeneration - prevention & control; Nerve Growth Factors - genetics; Nerve Growth Factors - pharmacology; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neuroprotective Agents - pharmacology; Parkinson; Parkinson Disease - complications; Parkinson Disease - etiology; Parkinson Disease - pathology; Rats; Rats, Wistar; Substantia nigra; Synucleins; Tyrosine-hydroxylase; α-synuclein
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1016/j.nbd.2004.06.008

Viral delivery of glial cell line-derived neurotrophic factor (GDNF) currently represents one of the most promising neuroprotective strategies for Parkinson's Disease (PD). However, the effect of this neurotrophic factor has never been tested in the newly available genetic models of PD based on the viral expression of mutated α-synuclein. In this study, we evaluated the ability of lentiviral vectors coding for GDNF (lenti-GDNF) to prevent nigral dopaminergic degeneration associated with the lentiviral mediated expression of the A30P mutant human α-synuclein (lenti-A30P). This virally based rat model develops a progressive and selective loss of dopamine neurons associated with the appearance of α-synuclein containing inclusions, thus recapitulating the major hallmarks of PD. Lenti-GDNF was injected in the substantia nigra 2 weeks before nigral administration of lenti-A30P. Although a robust expression of GDNF was observed in the whole nigrostriatal pathway due to retrograde and/or anterograde transport, lenti-GDNF did not prevent the α-synuclein-induced dopaminergic neurodegeneration in the lentiviral-based genetic rat model of PD. These results suggest that sustained GDNF treatment cannot modulate the cellular toxicity related to abnormal folded protein accumulation as mutated human α-synuclein.