期刊
JOURNAL OF CELL SCIENCE
卷 130, 期 2, 页码 325-331出版社
COMPANY OF BIOLOGISTS LTD
DOI: 10.1242/jcs.194241
关键词
Alpha-synuclein; Sideroflexin 3; Neurodegeneration; Synapse; Mitochondria
类别
资金
- Biotechnology and Biological Sciences Research Council
- GlaxoSmithKline CASE Studentship
- BBSRC DTP Studentship
- BBSRC [BB/J004332/1]
- Medical Research Council (MRC) [MR/M010341/1]
- MRC [MR/J012831/1]
- Wellcome Trust [100981/Z/13/Z]
- BBSRC [BBS/E/D/20251969] Funding Source: UKRI
- MRC [MR/J012831/1, MR/K017047/1, MR/M010341/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [1730606, 1358987, BBS/E/D/20251969] Funding Source: researchfish
- Medical Research Council [MR/K017047/1, MR/J012831/1, MR/M010341/1] Funding Source: researchfish
- Parkinson's UK [F-0902, K-1205] Funding Source: researchfish
- Wellcome Trust [100981/Z/13/Z] Funding Source: researchfish
alpha-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 alpha-synuclein controls synaptic stability and degeneration are not fully understood. Here, comparative proteomics on synapses isolated from alpha-synuclein(-/-) mouse brain identified mitochondrial proteins as primary targets of alpha-synuclein, revealing 37 mitochondrial proteins not previously linked to alpha-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 alpha-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.
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