Elucidation of cell death mechanism by dominant negative ofmutant LRRK2, the causative molecule of Parkinson's disease

突变型富含亮氨酸重复序列激酶2（LRRK2）是导致常染色体显性帕金森病（PD）的分子。在本研究中，我们发现野生型LRRK2蛋白的寿命缩短形成异源二聚体与I2020 T LRRK2。我们还证明了WT LRRK2对Akt1磷酸化的激酶活性因I2020 T LRRK2的存在而减弱。此外，WT LRRK2对H2O2诱导的细胞凋亡的保护作用通过与I2020T LRRK2共转染而受损。这些结果为LRRK2突变引起的PD病因学提供了新的见解，即，由异二聚体形成引起的显性负效应。

Mutant Leucine-rich repeat kinase 2 (LRRK2) is the molecule responsible for autosomal dominant Parkinson’s disease (PD). In the present study, we found that the lifetime of WT LRRK2 protein was shortened by formation of a heterodimer with I2020T LRRK2. We also demonstrated that the kinase activity of WT LRRK2 for phosphorylation of Akt1 was diminished by the presence of I2020T LRRK2. Furthermore, the protective effect of WT LRRK2 against H2O2-induced apoptosis was impaired by co-transfection with I2020T LRRK2. These results provide a new insight into the etiology of PD caused by the LRRK2 mutation, i.e., a dominant-negative effect resulting from heterodimer formation.