α-Synuclein and mitochondria: partners in crime?

Abstract

Increased α-synuclein levels and mutations in mitochondria-associated proteins both cause familial Parkinson's disease (PD), and synuclein and mitochondria also play central, but poorly understood, roles in the pathogenesis of idiopathic PD. A fraction of synuclein interacts with mitochondria, and synuclein can produce mitochondrial fragmentation and impair mitochondrial complex I activity. However, the consequences of these mitochondrial changes for bioenergetic and other mitochondrial functions remain poorly defined, as does the role of synuclein-mitochondria interactions in the normal and pathologic effects of synuclein. Understanding the functional consequences of synuclein's interactions with mitochondria is likely to provide important insights into disease pathophysiology, and may also reveal therapeutic strategies.

Fig. 1

Hypothetical schema of synuclein interactions with mitochondria normally and in Parkinson’s disease (PD). Under normal conditions, most synuclein is cytosolic in transiently “closed” conformations. However, a fraction of synuclein binds to mitochondria and is stabilized in a relatively “open” conformation [17]. In PD, synuclein levels are increased and a higher proportion of synuclein may exist in an oligomeric conformation, which also interacts with mitochondria [25, 48]. Increased synuclein monomers and/or oligomers drive increased mitochondrial fission, leading to more fragmented mitochondrial morphology. ER = endoplasmic reticulum

Fig. 2

Intersecting effects of synuclein and mitochondria on synaptic transmission and neuronal death? In healthy neurons, synuclein is believed to regulate neurotransmitter release. A fraction of synuclein also interacts with mitochondria, but the consequences of this interaction for mitochondrial function or synaptic transmission are unknown. In Parkinson’s disease, a greater fraction of synuclein interacts with mitochondria, and subsequent impairments in mitochondrial function may adversely affect synaptic transmission and predispose to neuronal death