Abstract
ABSTRACTα-Synuclein plays a central role in Parkinson's disease, where it contributes to the vulnerability of synapses to degeneration. However, the downstream mechanisms through which α-synuclein controls synaptic stability and degeneration are not fully understood. Here, comparative proteomics on synapses isolated from α-synuclein−/− mouse brain identified mitochondrial proteins as primary targets of α-synuclein, revealing 37 mitochondrial proteins not previously linked to α-synuclein or neurodegeneration pathways. Of these, sideroflexin 3 (SFXN3) was found to be a mitochondrial protein localized to the inner mitochondrial membrane. Loss of SFXN3 did not disturb mitochondrial electron transport chain function in mouse synapses, suggesting that its function in mitochondria is likely to be independent of canonical bioenergetic pathways. In contrast, experimental manipulation of SFXN3 levels disrupted synaptic morphology at the Drosophila neuromuscular junction. These results provide novel insights into α-synuclein-dependent pathways, highlighting an important influence on mitochondrial proteins at the synapse, including SFXN3. We also identify SFXN3 as a new mitochondrial protein capable of regulating synaptic morphology in vivo.
Highlights
INTRODUCTION αSynuclein is an abundant neuronal protein with a central role in the pathophysiology of Parkinson’s disease
The remaining 200 proteins were submitted to bioinformatics pathway analysis through ingenuity pathway analysis (IPA), DAVID and VarElect, revealing a striking enrichment of proteins (74 out of 200) belonging to mitochondrial pathways (Table 1; Table S1)
Further bioinformatics analysis identified 37 mitochondrial proteins not previously associated with α-synuclein or neurodegeneration (Fig. S1)
Summary
INTRODUCTION αSynuclein is an abundant neuronal protein with a central role in the pathophysiology of Parkinson’s disease. Α-synuclein has previously been shown to affect mitochondrial functions including complex I activity, oxidative stress and protein import pathways (Di Maio et al, 2016; Liu et al, 2009; Parihar et al, 2008).
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