αSynuclein and Mitochondrial Dysfunction: A Pathogenic Partnership in Parkinson's Disease?

Abstract

Parkinson's Disease (PD) is a complex, chronic, progressive, and debilitating neurodegenerative disorder. Neither a cure nor effective long-term therapy exist and the lack of knowledge of the molecular mechanisms responsible for PD development is a major impediment to therapeutic advances. The protein αSynuclein is a central component in PD pathogenesis yet its cellular targets and mechanism of toxicity remains unknown. Mitochondrial dysfunction is also a common theme in PD patients and this review explores the strong possibility that αSynuclein and mitochondrial dysfunction have an inter-relationship responsible for underlying the disease pathology. Amplifying cycles of mitochondrial dysfunction and αSynuclein toxicity can be envisaged, with either being the disease-initiating factor yet acting together during disease progression. Multiple potential mechanisms exist in which mitochondrial dysfunction and αSynuclein could interact to exacerbate their neurodegenerative properties. Candidates discussed within this review include autophagy, mitophagy, mitochondrial dynamics/fusion/fission, oxidative stress and reactive oxygen species, endoplasmic reticulum stress, calcium, nitrosative stress and αSynuclein Oligomerization.

Figure 1

The interrelationship between mitochondrial dysfunction and αSynuclein toxicity. αSynuclein toxicity, directly or indirectly, impairs mitochondrial function (A). A prominent result of this dysfunction is the production of reactive oxygen species (ROS) which can be counteracted by the cellular ROS buffering systems. However prolonged mitochondrial stress, exacerbated by αSynuclein, has the potential to deplete this buffering capacity, and the resulting increase of cellular ROS has multiple damaging effects such as the modification of αSynuclein (B). Modified αSynuclein can inhibit chaperone-mediated autophagy (CMA), increasing the proteins toxicity by its inefficient clearance. αSynuclein toxicity is dose dependant, and excessive amounts of αSynuclein have the potential to block autophagy pathways (i.e., macroautophagy and mitophagy). This results in an accumulation of dysfunctional mitochondria due to inefficient clearance (C). αSynuclein toxicity can also increase mitochondrial fission and inhibit mitochondrial fusion (D). Both the increase in mitochondrial fragmentation and the inability of mitochondria to rejoin the mitochondrial network result in an increase in dysfunctional, depolarised mitochondria. αSynuclein toxicity also blocks endoplasmic reticulum (ER) to Golgi trafficking resulting in ER stress. When under constant and prolonged stress, the ER releases Ca²⁺ into the cytosol. Due to mitochondrial-ER contact sites, mitochondria readily buffer cytosolic Ca²⁺; however, excess Ca²⁺ in the mitochondria causes mitochondrial stress (E). Dysfunctional mitochondria in turn release Ca²⁺ into the cytosol causing further ER stress. Mitochondrial dysfunction may exacerbate αSynuclein toxicity (F), with both acting synergistically to enhance each other in a self-amplifying cycle over prolonged periods of time, resulting in multiple downstream effects, including cell death as seen in PD.