Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA.
Hum Mol Genet. 2012 May 1;21(9):1931-44. doi: 10.1093/hmg/dds003. Epub 2012 Jan 6.
The leucine-rich repeat kinase 2 (LRRK2) mutations are the most common cause of autosomal-dominant Parkinson disease (PD). Mitochondrial dysfunction represents a critical event in the pathogenesis of PD. We demonstrated that wild-type (WT) LRRK2 expression caused mitochondrial fragmentation along with increased mitochondrial dynamin-like protein (DLP1, also known as DRP1), a fission protein, which was further exacerbated by expression of PD-associated mutants (R1441C or G2019S) in both SH-SY5Y and differentiated primary cortical neurons. We also found that LRRK2 interacted with DLP1, and LRRK2-DLP1 interaction was enhanced by PD-associated mutations that probably results in increased mitochondrial DLP1 levels. Co-expression of dominant-negative DLP1 K38A or WT Mfn2 blocked LRRK2-induced mitochondrial fragmentation, mitochondrial dysfunction and neuronal toxicity. Importantly, mitochondrial fragmentation and dysfunction were not observed in cells expressing either GTP-binding deficient mutant LRRK2 K1347A or kinase-dead mutant D1994A which has minimal interaction with DLP1 and did not increase the mitochondrial DLP1 level. We concluded that LRRK2 regulates mitochondrial dynamics by increasing mitochondrial DLP1 through its direct interaction with DLP1, and LRRK2 kinase activity plays a critical role in this process.
富含亮氨酸重复激酶 2（LRRK2）突变是常染色体显性遗传帕金森病（PD）最常见的原因。线粒体功能障碍是 PD 发病机制中的一个关键事件。我们证明，野生型（WT）LRRK2 的表达会导致线粒体碎片化，同时增加线粒体动力相关蛋白 1（DLP1，也称为 DRP1），一种分裂蛋白，在 SH-SY5Y 和分化的原代皮质神经元中，由与 PD 相关的突变体（R1441C 或 G2019S）表达进一步加剧。我们还发现 LRRK2 与 DLP1 相互作用，与 PD 相关的突变增强了 LRRK2-DLP1 的相互作用，可能导致线粒体 DLP1 水平升高。显性负性 DLP1 K38A 或 WT Mfn2 的共表达阻断了 LRRK2 诱导的线粒体碎片化、线粒体功能障碍和神经元毒性。重要的是，在表达 GTP 结合缺陷突变体 LRRK2 K1347A 或激酶失活突变体 D1994A 的细胞中没有观察到线粒体碎片化和功能障碍，这两种突变体与 DLP1 的相互作用最小，并且不会增加线粒体 DLP1 水平。我们得出的结论是，LRRK2 通过其与 DLP1 的直接相互作用增加线粒体 DLP1 来调节线粒体动力学，而 LRRK2 激酶活性在这个过程中起着关键作用。
