Elucidation of cell death mechanism by mutant LRRK2, the causative molecule of familial Parkinson's disease

突变的LRRK2是常染色体显性遗传性家族性帕金森病的致病分子。在本研究中，我们证明了与野生型(WT)分子相比，I2020T LRRK2对过氧化氢诱导的细胞凋亡的保护作用减弱。脉冲追逐实验也证明了I2020T LRRK2分子比WT或G2019S LRRK2具有更高的降解速率。加入蛋白酶体和溶酶体抑制剂后，I2020T突变体LRRK2的蛋白质水平达到WT LRRK2的水平，同时突变体LRRK2对细胞凋亡的保护作用增强。我们进一步证实，通过敲除WT LRRK2的细胞内蛋白水平的降低导致了对细胞凋亡的保护作用的降低。

Mutant LRRK2 is the causal molecule for autosomal dominant familial Parkinson's disease. In the present study, we demonstrated that the protective effect of I2020T LRRK2 against hydrogen peroxide-induced apoptosis was impaired in comparison with the wild-type (WT) molecule. Also, Pulse-chase experiments proved that the I2020T LRRK2 molecule has a higher degradation rate than WT or G2019S LRRK2. Upon addition of proteasome and lysosome inhibitors, the protein level of I2020T mutant LRRK2 reached that of WT LRRK2, and simultaneously the mutant LRRK2 exhibited an elevated protective effect against apoptosis. We further confirmed that a decrease in the intracellular protein level of WT LRRK2 by knocking down resulted in a reduction of protectivity against apoptosis.