Abstract
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 α-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 Ca2+-ATPase (SERCA) and suppress its activity by preventing displacement of phospholamban (PLN). LRRK2-GS–mediated SERCA malfunction leads to ER Ca2+ depletion, which induces the formation of mitochondria-ER contacts and subsequent Ca2+ overload in mitochondria, ultimately resulting in mitochondrial dysfunction. Collectively, our data suggest that, in astrocytes, LRRK2-GS impairs ER Ca2+ homeostasis, which determines cell survival, and as a result, could contribute to the development of PD.
Highlights
Parkinson’s disease (PD), the second-most common neurodegenerative disease, is characterized by selective loss of dopaminergic (DA) neurons of the substantia nigra pars compacta (SNpc), accumulation of intracellular inclusions containing α-synuclein, and subsequent progressive impairment of dopaminergic neurons—the clinical feature of PD [6, 58]
We found that both types of α-synuclein induced apoptotic PKR-like endoplasmic reticulum kinase (PERK)-CCAAT/enhancer-binding protein homologous protein (CHOP) signaling in leucine-rich repeat kinase 2 protein (LRRK2)-GS astrocytes, as evidenced by increases in mRNA and protein levels of the endoplasmic reticulum (ER) stress markers (Fig. 1 a-b)
Similar results were obtained following challenge with the ER-stress–inducing agent, tunicamycin (Additional file 2: Figure S1 c–f). These results show that ER-stress–mediated cell death is significantly increased in LRRK2-GS astrocytes after α-synuclein treatment
Summary
Parkinson’s disease (PD), the second-most common neurodegenerative disease, is characterized by selective loss of dopaminergic (DA) neurons of the substantia nigra pars compacta (SNpc), accumulation of intracellular inclusions containing α-synuclein, and subsequent progressive impairment of dopaminergic neurons—the clinical feature of PD [6, 58]. It is mostly sporadic; less than 10% of PD cases are inherited [28]. Since ER resident chaperones are involved in protein folding require high Ca2+ concentrations for their activity, altered ER Ca2+ homeostasis can result in an imbalance between the capacity of the protein processing machinery and the amount of unfolded proteins
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