α‐Synuclein induces unfolded protein response via distinct signaling pathway independent of er‐membrane kinases

Abastract Parkinson's disease (PD) is a neurodegenerative disease caused by selective degeneration of dopaminergic neurons in the substantia nigra. Mutations in α‐synuclein have been causally linked to the pathogenesis of hereditary PD. In addition, it is a major component of Lewy body found in the brains of sporadic cases as well. In the present study, we examined whether overexpression of wild type or PD‐related mutant α‐synuclein induces unfolded protein response (UPR) and triggers the known signaling pathway of the resulting endoplasmic reticulum (ER) stress in SH‐SY5Y cells. Overexpression of wild type, A30P, and A53T α‐synuclein all induced XBP‐1 mRNA splicing, one of the late stage UPR events. However, activation of ER membrane kinases and upregulation of ER or cytoplsmic chaperones were not detected when α‐synuclein was overexpressed. However, basal level of cytoplsmic calcium was elevated in α‐synuclein‐expressing cells. Our observation suggests that overexpression of α‐synuclein induces UPR independent of the known ER membrane kinase‐mediated signaling pathway and induces ER stress by disturbing calcium homeostasis.