A Rat Model of Progressive Nigral Neurodegeneration Induced by the Parkinson's Disease-Associated G2019S Mutation in LRRK2

• DOI: 10.1523/jneurosci.5092-10.2011
• Publication Date: 2011-01-19T17:33:21Z
• Authors: Julien Dusonchet; Olexiy Kochubey; Klodjan Stafa; Samuel M. Young; Romain Zufferey; Darren J. Moore; Bernard L. Schneider; Patrick Aebischer
• Keywords: Neurons; Analysis of Variance; Dopamine; Blotting, Western; Brain; Expression; Cell Count; Parkinson Disease; Adenoviral Vectors; Protein Serine-Threonine Kinases; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Immunohistochemistry; Rats; Mice; Disease Models, Animal; 03 medical and health sciences; 0302 clinical medicine; Mutation; Nerve Degeneration; Animals; Female; Rats, Wistar

The G2019S mutation in the leucine-rich repeat kinase 2 (LRRK2) gene is the most common genetic cause of Parkinson's disease (PD), accounting for a significant proportion of both autosomal dominant familial and sporadic PD cases. Our aim in the present study is to generate a mammalian model of mutant G2019S LRRK2 pathogenesis, which reproduces the robust nigral neurodegeneration characteristic of PD. We developed adenoviral vectors to drive neuron-specific expression of full-length wild-type or mutant G2019S human LRRK2 in the nigrostriatal system of adult rats. Wild-type LRRK2 did not induce any significant neuronal loss. In contrast, under the same conditions and levels of expression, G2019S mutant LRRK2 causes a progressive degeneration of nigral dopaminergic neurons. Our data provide a novel rat model of PD, based on a prevalent genetic cause, that reproduces a cardinal feature of the disease within a rapid time frame suitable for testing of neuroprotective strategies.