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.
Keywords: Alanine/genetics/metabolism ; Animals ; Brain/metabolism/pathology ; Disease Models ; Animal ; Dopamine/ metabolism ; Female ; Gene Expression ; Gene Therapy ; Genetic Vectors/genetics ; Lentivirus/ genetics ; Mutation/genetics ; Nerve Tissue Proteins/genetics/ metabolism ; Neurons/metabolism/pathology ; Parkinson Disease/genetics/ metabolism/ pathology/therapy ; Phosphorylation ; Rats ; Rats ; Wistar ; Synucleins ; Ubiquitin-Protein Ligases/genetics/ metabolism ; alpha-Synuclein ; Animal ; Rats
Institute of Neuroscience, Swiss Federal Institute of Technology Lausanne, Ecole Polytechnique Federale de Lausanne, CH-1015 Lausanne, Switzerland.
Record created on 2007-03-09, modified on 2016-08-08