A new role for α-synuclein in Parkinson's disease: Alteration of ER-mitochondrial communication

Familial cases of Parkinson's disease (PD) can be associated with overexpression or mutation of α‐synuclein, a synaptic protein reported to be localized mainly in the cytosol and mitochondria. We recently showed that wild‐type α‐synuclein is not present in mitochondria, as previously thought, but rather is located in mitochondrial‐associated endoplasmic reticulum membranes. Remarkably, we also found that PD‐related mutated α‐synuclein results in its reduced association with mitochondria‐associated membranes, coincident with a lower degree of apposition of endoplasmic reticulum with mitochondria and an increase in mitochondrial fragmentation, as compared with wild‐type. This new subcellular localization of α‐synuclein raises fundamental questions regarding the relationship of α‐synuclein to mitochondria‐associated membranes function, in both normal and pathological states. In this article, we attempt to relate aspects of PD pathogenesis to what is known about mitochondria‐associated membranes' behavior and function. We hypothesize that early events occurring in dopaminergic neurons at the level of the mitochondria‐associated membranes could cause long‐term disturbances that lead to PD. © 2015 International Parkinson and Movement Disorder Society