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.


Published in:
Proc Natl Acad Sci U S A, 101, 50, 17510-5
Year:
2004
ISSN:
0027-8424
Keywords:
Note:
Institute of Neuroscience, Swiss Federal Institute of Technology Lausanne, Ecole Polytechnique Federale de Lausanne, CH-1015 Lausanne, Switzerland.
Laboratories:




 Record created 2007-03-09, last modified 2018-03-17


Rate this document:

Rate this document:
1
2
3
 
(Not yet reviewed)