Parkin protects against neurotoxicity in the 6-hydroxydopamine rat model for Parkinson's disease.
Loss-of-function mutations in the PARK2 gene are the major cause of early onset familial Parkinson's disease. The gene product, parkin, is an E3 ligase of the ubiquitin-proteasome pathway involved in protein degradation. Dopaminergic neuron loss may result from the toxic accumulation of parkin substrates, suggesting a key role for parkin in dopaminergic neuron survival. In this study, we have investigated the neuroprotective capacity of parkin in the 6-OHDA rat model for Parkinson's disease. 6-OHDA induces the generation of reactive oxygen species leading to the degeneration of catecholaminergic neurons, but may also impair proteasome activity. Lentiviral vectors encoding human wild-type parkin or green fluorescent protein were stereotactically injected into the substantia nigra 2 weeks prior to a striatal 6-OHDA lesion. Histological analysis 1 and 3 weeks after lesioning showed a significant preservation of dopaminergic cell bodies and nerve terminals. Moreover, lesioned rats overexpressing parkin displayed a corresponding behavioral improvement as measured by the amphetamine-induced rotation test and the cylinder test. The improved performance in the amphetamine-induced rotation test lasted until 20 weeks after lesioning. Our results demonstrate that parkin acts as a potent neuroprotective agent in vivo against 6-OHDA toxic insults. These data support the therapeutic potential of parkin for the treatment of not only familial but also sporadic Parkinson's disease.
Vercammen
Linda
L
Laboratory for Neurobiology and Gene Therapy, Molecular Medicine, K.U. Leuven, Kapucijnenvoer 33 VCTB+5, B-3000 Leuven, Flanders, Belgium.
Van der Perren
Anke
A
Vaudano
Elisabetta
E
Gijsbers
Rik
R
Debyser
Zeger
Z
Van den Haute
Chris
C
Baekelandt
Veerle
V
D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D009043:Motor Activity / Q000187:drug effects; D016627:Oxidopamine / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D010300:Parkinson Disease / Q000378:metabolism* / Q000473:pathology*; D051381:Rats; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
D016627:Oxidopamine; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein