The mitochondrial protein Sideroflexin 3 (SFXN3) influences neurodegeneration pathways in vivo
Leire M. Ledahawskya b c d, Maria Eirini Terzenidoue f, Ruairidh Edwardse f, Rachel Klineb d g h, Laura C. Grahamb d g h, Samantha L. Eatonb d g h, Dinja van der Hoorna b c d, Helena Chaytowa b c d, Yuting Huanga b c d, Ewout J. N. Groena b c d i j, Anna A. L. Motyla b c d, Douglas J. Lamont
- aEdinburgh Medical School Biomedical Sciences University of Edinburgh UK
- bEuan MacDonald Centre for Motor Neuron Disease Research University of Edinburgh UK
- cEdinburgh Medical School, Biomedical Sciences, University of Edinburgh, UK
- dEuan MacDonald Centre for Motor Neuron Disease Research, University of Edinburgh, UK
- eInstitute of Molecular Cell and Systems Biology College of Medical, Veterinary and Life Sciences University of Glasgow UK
- fInstitute of Molecular Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, UK
- gThe Roslin Institute and R(D)SVS University of Edinburgh UK
- hThe Roslin Institute and R(D)SVS, University of Edinburgh, UK
- iDepartment of Neurology and Neurosurgery UMC Utrecht Brain Center The Netherlands
- jDepartment of Neurology and Neurosurgery, UMC Utrecht Brain Center, The Netherlands
- k
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Abstract
Synapses are a primary pathological target in neurodegenerative diseases. Identifying therapeutic targets at the synapse could delay progression of numerous conditions. The mitochondrial protein SFXN3 is a neuronally enriched protein expressed in synaptic terminals and regulated by key synaptic proteins, including α-synuclein. We first show that SFXN3 uses the carrier import pathway to insert into the inner mitochondrial membrane. Using high-resolution proteomics on Sfxn3-KO mice synapses, we then demonstrate that SFXN3 influences proteins and pathways associated with neurodegeneration and cell death (including CSPα and Caspase-3), as well as neurological conditions (including Parkinson's disease and Alzheimer's disease). Overexpression of SFXN3 orthologues in Drosophila models of Parkinson's disease significantly reduced dopaminergic neuron loss. In contrast, the loss of SFXN3 was insufficient to trigger neurodegeneration in mice, indicating an anti- rather than pro-neurodegeneration role for SFXN3. Taken together, these results suggest a potential role for SFXN3 in the regulation of neurodegeneration pathways.
TL;DRIt is demonstrated that SFXN3 influences proteins and pathways associated with neurodegeneration and cell death (including CSPα and Caspase‐3), as well as neurological conditions (including Parkinson's disease and Alzheimer’s disease). (Semantic Scholar)