A new role for -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 -synuclein, a synaptic protein reported to be localized mainly in the cytosol and mitochondria. We recently showed that wild-type -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 -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 -synuclein raises fundamental questions regarding the relationship of -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. (c) 2015 International Parkinson and Movement Disorder Society