Regulation of LRRK2 Stability by the E3 Ubiquitin Ligase CHIP

Dominantly inherited mutations in the leucine-rich repeat kinase 2 gene (LRRK2) are the most common cause of familial Parkinson's disease (PD) and have also been identified in individuals with sporadic PD. Although the exact cellular function of LRRK2 remains unknown, most PD-linked mutations appear to be toxic to cells in culture via mechanisms that depend on the kinase activity of LRRK2 or on the formation of cytoplasmic inclusions. Here we show that the E3 ubiquitin ligase CHIP physically associates with LRRK2 and regulates the cellular abundance of LRRK2. We further show that LRRK2 forms a complex with overexpressed and endogenous CHIP and Hsp90. Our data indicates that the destabilization of LRRK2 by CHIP is due to ubiquitination and proteasome-dependent degradation. Hsp90 can attenuate CHIP-mediated degradation and this can be blocked by the Hsp90 inhibitor geldanamycin. These findings provide important insight into the cellular regulation of LRRK2 stability and may lead to the development of therapeutics to treat PD based on controlling LRRK2 stability.

富亮氨酸重复激酶2基因（LRRK2）的显性遗传突变是家族性帕金森病（PD）最常见的致病原因，同时也在散发性帕金森病患者中被检出。尽管LRRK2的确切细胞功能尚未明确，但大多数与PD相关的突变似乎通过依赖于LRRK2激酶活性或胞质包涵体形成的机制，对培养中的细胞产生毒性。本研究发现，E3泛素连接酶CHIP可与LRRK2发生物理结合，并调控LRRK2的细胞丰度。我们进一步证实，LRRK2可与过表达及内源性的CHIP和Hsp90形成复合物。我们的数据表明，CHIP介导的LRRK2稳定性降低是通过泛素化及蛋白酶体依赖性降解实现的。Hsp90可减弱CHIP介导的降解过程，且该作用可被Hsp90抑制剂格尔德霉素阻断。上述发现为LRRK2稳定性的细胞调控机制提供了重要见解，或可推动基于调控LRRK2稳定性的PD治疗药物开发。