Alpha-Synuclein Effects on Mitochondrial Quality Control in Parkinson's Disease

Abstract

The maintenance of healthy mitochondria is essential for neuronal survival and relies upon mitochondrial quality control pathways involved in mitochondrial biogenesis, mitochondrial dynamics, and mitochondrial autophagy (mitophagy). Mitochondrial dysfunction is critically implicated in Parkinson's disease (PD), a brain disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra. Consequently, impaired mitochondrial quality control may play a key role in PD pathology. This is affirmed by work indicating that genes such as PRKN and PINK1, which participate in multiple mitochondrial processes, harbor PD-associated mutations. Furthermore, mitochondrial complex-I-inhibiting toxins like MPTP and rotenone are known to cause Parkinson-like symptoms. At the heart of PD is alpha-synuclein (αS), a small synaptic protein that misfolds and aggregates to form the disease's hallmark Lewy bodies. The specific mechanisms through which aggregated αS exerts its neurotoxicity are still unknown; however, given the vital role of both αS and mitochondria to PD, an understanding of how αS influences mitochondrial maintenance may be essential to elucidating PD pathogenesis and discovering future therapeutic targets. Here, the current knowledge of the relationship between αS and mitochondrial quality control pathways in PD is reviewed, highlighting recent findings regarding αS effects on mitochondrial biogenesis, dynamics, and autophagy.

Keywords: PGC-1α; PINK1/Parkin; Parkinson’s disease; mitochondrial dysfunction; mitochondrial fragmentation; mitophagy; α-synuclein.

Figure 1

Potential pathological interactions of αS with mitochondrial quality control pathways in PD. (a) αS and mitochondrial biogenesis. (i) αS may act as a transcriptional modulator of PGC-1α under oxidative stress, binding to its promoter sequence to repress PGC-1α function. (ii) An excess of exogenous αS oligomers and fibrils may interfere with Parkin’s degradation of PARIS, thus increasing the PARIS-mediated transcriptional repression of PGC-1α. (b) αS and mitochondrial dynamics. (i) Pathogenic αS may increase the cleavage of OPA1 in mitochondrial fusion. (ii) αS-induced alterations to mitochondrial fission may be independent of or dependent upon DRP1: αS may interact directly with mitochondrial membranes or may increase the translocation of DRP1 to mitochondria. (c) αS and mitochondrial autophagy. (i) The overexpression of αS may stabilize Miro proteins, which are required for the formation of mitochondrial-derived vesicles (MDVs). (ii) αS may downregulate Parkin expression and activity as described above, having negative impacts on MDV trafficking. (iii) During autophagosome formation in mitophagy, αS may aberrantly stabilize Miro at the OMM as previously described, causing delays in mitophagy initiation. αS may also impact autophagosome formation by causing a reduction in Parkin levels, affecting the ubiquitination of mitochondrial proteins. (iv) By binding to spectrin, αS may excessively stabilize the actin cytoskeleton, resulting in the mislocalization of key proteins involved in autophagosome trafficking. This mislocalization may also have global effects, disrupting other forms of cellular trafficking. (v) Overexpressed αS may decrease SNAP29 activity, affecting the SNARE complex that mediates autophagosome–lysosome fusion during the last step of mitophagy. Figure created with BioRender. Partially adapted from Thorne and Tumbarello [32].