Department of Neuroscience, University of Connecticut School of Medicine, Farmington, CT 06030, USA.
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Sci Adv. 2024 Nov 22;10(47):eadn5417. doi: 10.1126/sciadv.adn5417.
Mutations in are the most common genetic cause of Parkinson's disease (PD). LRRK2 protein contains two enzymatic domains: a GTPase (Roc-COR) and a kinase domain. Disease-causing mutations are found in both domains. Now, studies have focused largely on LRRK2 kinase activity, while attention to its GTPase function is limited. LRRK2 is a guanine nucleotide-binding protein, but the mechanism of direct regulation of its GTPase activity remains unclear and its physiological GEF is not known. Here, we identified CalDAG-GEFI (CDGI) as a physiological GEF for LRRK2. CDGI interacts with LRRK2 and increases its GDP to GTP exchange activity. CDGI modulates LRRK2 cellular functions and LRRK2-induced neurodegeneration in both LRRK2 and mouse models. Together, this study identified the physiological GEF for LRRK2 and provides strong evidence that LRRK2 GTPase is regulated by GAPs and GEFs. The LRRK2 GTPase, GAP, or GEF activities have the potential to serve as therapeutic targets, which is distinct from the direct LRRK2 kinase inhibition.
是帕金森病（PD）最常见的遗传原因。LRRK2 蛋白包含两个酶结构域：GTPase（Roc-COR）和激酶结构域。这两个结构域都存在致病突变。现在，研究主要集中在 LRRK2 激酶活性上，而对其 GTPase 功能的关注有限。LRRK2 是一种鸟嘌呤核苷酸结合蛋白，但直接调节其 GTPase 活性的机制尚不清楚，其生理 GEF 也未知。在这里，我们鉴定出 CalDAG-GEFI（CDGI）是 LRRK2 的生理 GEF。CDGI 与 LRRK2 相互作用，增加其 GDP 到 GTP 交换活性。CDGI 调节 LRRK2 的细胞功能和 LRRK2 在 和小鼠模型中的神经退行性变。总之，这项研究鉴定了 LRRK2 的生理 GEF，并提供了强有力的证据表明 LRRK2 GTPase 受到 GAP 和 GEF 的调节。LRRK2 GTPase、GAP 或 GEF 的活性有可能成为治疗靶点，这与直接抑制 LRRK2 激酶活性不同。
