Lentiviral vector delivery of parkin prevents dopaminergic degeneration in an alpha-synuclein rat model of Parkinson's disease |
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Authors: | Lo Bianco Christophe Schneider Bernard L Bauer Matthias Sajadi Ali Brice Alexis Iwatsubo Takeshi Aebischer Patrick |
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Affiliation: | Institute of Neuroscience, Swiss Federal Institute of Technology Lausanne, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland. |
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Abstract: | Parkinson's disease (PD) is characterized by a progressive loss of midbrain dopamine neurons and the presence of cytoplasmic inclusions called Lewy bodies. Mutations in several genes including alpha-synuclein and parkin have been linked to familial PD. The loss of parkin's E3-ligase activity leads to dopaminergic neuronal degeneration in early-onset autosomal recessive juvenile parkinsonism, suggesting a key role of parkin for dopamine neuron survival. To evaluate the potential neuroprotective role of parkin in the pathogenesis of PD, we tested whether overexpression of wild-type rat parkin could protect against the toxicity of mutated human A30P alpha-synuclein in a rat lentiviral model of PD. Animals overexpressing parkin showed significant reductions in alpha-synuclein-induced neuropathology, including preservation of tyrosine hydroxylase-positive cell bodies in the substantia nigra and sparing of tyrosine hydroxylase-positive nerve terminals in the striatum. The parkin-mediated neuroprotection was associated with an increase in hyperphosphorylated alpha-synuclein inclusions, suggesting a key role for parkin in the genesis of Lewy bodies. These results indicate that parkin gene therapy may represent a promising candidate treatment for PD. |
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Keywords: | gene therapy lentivirus neurodegenerative disease Lewy body neuroprotection |
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