| First Author | Lee JH | Year | 2019 |
| Journal | Acta Neuropathol Commun | Volume | 7 |
| Issue | 1 | Pages | 68 |
| PubMed ID | 31046837 | Mgi Jnum | J:277876 |
| Mgi Id | MGI:6355873 | Doi | 10.1186/s40478-019-0716-4 |
| Citation | Lee JH, et al. (2019) Parkinson's disease-associated LRRK2-G2019S mutant acts through regulation of SERCA activity to control ER stress in astrocytes. Acta Neuropathol Commun 7(1):68 |
| abstractText | Accumulating evidence indicates that endoplasmic reticulum (ER) stress is a common feature of Parkinson's disease (PD) and further suggests that several PD-related genes are responsible for ER dysfunction. However, the underlying mechanisms are largely unknown. Here, we defined the mechanism by which LRRK2-G2019S (LRRK2-GS), a pathogenic mutation in the PD-associated gene LRRK2, accelerates ER stress and cell death. Treatment of cells with alpha-synuclein increased the expression of ER stress proteins and subsequent cell death in LRRK2-GS astrocytes. Intriguingly, we found that LRRK2-GS localizes to the ER membrane, where it interacts with sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA) and suppress its activity by preventing displacement of phospholamban (PLN). LRRK2-GS-mediated SERCA malfunction leads to ER Ca(2+) depletion, which induces the formation of mitochondria-ER contacts and subsequent Ca(2+) overload in mitochondria, ultimately resulting in mitochondrial dysfunction. Collectively, our data suggest that, in astrocytes, LRRK2-GS impairs ER Ca(2+) homeostasis, which determines cell survival, and as a result, could contribute to the development of PD. |
