Lo Bianco, C.Schneider, B. L.Bauer, M.Sajadi, A.Brice, A.Iwatsubo, T.Aebischer, P.2007-03-092007-03-092007-03-09200410.1073/pnas.0405313101https://infoscience.epfl.ch/handle/20.500.14299/3771WOS:000225803400037Parkinson'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.Alanine/genetics/metabolismAnimalsBrain/metabolism/pathologyDisease ModelsAnimalDopamine/ metabolismFemaleGene ExpressionGene TherapyGenetic Vectors/geneticsLentivirus/ geneticsMutation/geneticsNerve Tissue Proteins/genetics/ metabolismNeurons/metabolism/pathologyParkinson Disease/genetics/ metabolism/ pathology/therapyPhosphorylationRatsRatsWistarSynucleinsUbiquitin-Protein Ligases/genetics/ metabolismalpha-SynucleinAnimalRatstext::journal::journal article::research article