Lentiviral vector delivery of parkin prevents dopaminergic degeneration in an α-synuclein rat model of Parkinson's disease

C Lo Bianco, BL Schneider, M Bauer… - Proceedings of the …, 2004 - National Acad Sciences
C Lo Bianco, BL Schneider, M Bauer, A Sajadi, A Brice, T Iwatsubo, P Aebischer
Proceedings of the National Academy of Sciences, 2004National Acad Sciences
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 α-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 …
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 α-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 α-synuclein in a rat lentiviral model of PD. Animals overexpressing parkin showed significant reductions in α-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 α-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.
National Acad Sciences