I2020T leucine-rich repeat kinase 2, the causative mutant molecule of familial Parkinson's disease, has a higher intracellular degradation rate than the wild-type molecule

Leucine-rich repeat kinase 2 (LRRK2) has been identified as the causal gene for autosomal dominant familial Parkinson's disease (PD), although the mechanism of neurodegeneration involving the mutant LRRK2 molecules remains unknown. In the present study, we found that the protein level of transfected (IT)-T-2020 Mutant LRRK2 was significantly lower than that of wild-type and G(2019)S mutant LRRK2, although the intracellular localization of the (IT)-T-2020 and wild-type molecules did not differ. Pulse-chase experiments proved that the (IT)-T-2020 LRRK2 molecule has a higher degradation rate than wild-type or G(2019)S LRRK2. Upon addition of proteasome and lysosome inhibitors, the protein level of (IT)-T-2020 mutant LRRK2 reached that of the wild-type. These results indicate that (IT)-T-2020 mutant LRRK2 is more susceptible to post-translational degradation than the wild-type molecule. Our results indicate a novel molecular feature characteristic to (IT)-T-2020 LRRK2, and provide a new insight into the mechanism of neurodegeneration caused by LRRK2. (C) 2009 Elsevier Inc. All rights reserved.