CalDAG-GEFI acts as a guanine nucleotide exchange factor for LRRK2 to regulate LRRK2 function and neurodegeneration
Mutations in <i>LRRK2</i> 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 <i>Drosophila</i> 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.
Authors
- Jianzhong Yu (ORCID: https://orcid.org/0000-0002-4883-646X)
- Bingxu Huang (ORCID: https://orcid.org/0000-0002-6582-4612)
- Xin‐Ming Ma (ORCID: https://orcid.org/0000-0003-3496-3430)
- Ted M. Dawson (ORCID: https://orcid.org/0000-0002-6459-0893)
- Valina L. Dawson (ORCID: https://orcid.org/0000-0002-2915-3970)
- Yulan Xiong (ORCID: https://orcid.org/0000-0003-1649-7552)
- Gang Ma (ORCID: https://orcid.org/0000-0002-7551-1791)
- Noah Guy Lewis Guiberson (ORCID: https://orcid.org/0000-0002-7602-5402)
- Jill R. Crittenden (ORCID: https://orcid.org/0000-0002-1981-1917)
- Shifan Chen (ORCID: https://orcid.org/0000-0001-8522-7527)
- Qinfang Liu (ORCID: https://orcid.org/0000-0003-2930-3892)
- Ann M. Graybiel (ORCID: https://orcid.org/0000-0002-4326-7720)
- Dong Zhu (ORCID: https://orcid.org/0009-0008-2741-7160)
Institutions
- University of Connecticut (US)
- McGovern Institute for Brain Research (US)
- Johns Hopkins University (US)
- Johns Hopkins Medicine (US)
- Orthopaedic Research Foundation (US)
- Massachusetts Institute of Technology (US)
Publication Details
- Journal
- Science Advances
- Published
- 2024-11-22
- DOI
- https://doi.org/10.1126/sciadv.adn5417
- Citations
- 2
- Primary Topic
- Parkinson's Disease Mechanisms and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 0.74
Funders
- University of Connecticut
- University of Connecticut Health Center