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.
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