Lentiviral vector delivery of parkin prevents dopaminergic degeneration in an alpha-synuclein rat model of Parkinson's disease.
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.
Lo Bianco
Christophe
C
Institute of Neuroscience, Swiss Federal Institute of Technology Lausanne, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
Schneider
Bernard L
BL
Bauer
Matthias
M
Sajadi
Ali
A
Brice
Alexis
A
Iwatsubo
Takeshi
T
Aebischer
Patrick
P
D000409:Alanine / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics; D016086:Lentivirus / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology* / Q000628:therapy; D010766:Phosphorylation; D051381:Rats; D017208:Rats, Wistar; D051843:Synucleins; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D051844:alpha-Synuclein
D009419:Nerve Tissue Proteins; C497606:Snca protein, rat; D051843:Synucleins; D051844:alpha-Synuclein; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D000409:Alanine; D004298:Dopamine