A-Syn(ful) MAM: A Fresh Perspective on a Converging Domain in Parkinson's Disease

Parkinson's disease (PD) is a disease of an unknown origin. Despite that, decades of research have provided considerable evidence that alpha-synuclein (αSyn) is central to the pathogenesis of disease. Mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) are functional domains formed at contact sites between the ER and mitochondria, with a well-established function of MAMs being the control of lipid homeostasis within the cell. Additionally, there are numerous proteins localized or enriched at MAMs that have regulatory roles in several different molecular signaling pathways required for cellular homeostasis, such as autophagy and neuroinflammation. Alterations in several of these signaling pathways that are functionally associated with MAMs are found in PD. Taken together with studies that find αSyn localized at MAMs, this has implicated MAM (dys)function as a converging domain relevant to PD. This review will highlight the many functions of MAMs and provide an overview of the literature that finds αSyn, in addition to several other PD-related proteins, localized there. This review will also detail the direct interaction of αSyn and αSyn-interacting partners with specific MAM-resident proteins. In addition, recent studies exploring new methods to investigate MAMs will be discussed, along with some of the controversies regarding αSyn, including its several conformations and subcellular localizations. The goal of this review is to highlight and provide insight on a domain that is incompletely understood and, from a PD perspective, highlight those complex interactions that may hold the key to understanding the pathomechanisms underlying PD, which may lead to the targeted development of new therapeutic strategies.