title: Sideroflexin 3 is an α-synuclein-dependent mitochondrial protein that regulates synaptic morphology.
abstract: α-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.
authors.affiliation: Centre for Integrative Physiology, University of Edinburgh, Hugh Robson Building, Edinburgh, EH8 9XD, UK.|Euan MacDonald Centre for Motor Neurone Disease Research, Chancellor's Building, University of Edinburgh, Edinburgh, EH16 4SB, UK.
authors.forename: Inês S
authors.initials: IS
authors.lastname: Amorim
authors.affiliation: Euan MacDonald Centre for Motor Neurone Disease Research, Chancellor's Building, University of Edinburgh, Edinburgh, EH16 4SB, UK.|Division of Neurobiology, The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Edinburgh, EH25 9RG, UK.
authors.forename: Laura C
authors.initials: LC
authors.lastname: Graham
authors.affiliation: Molecular Metabolism Group, University/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburg, EH16 4TJ, UK.
authors.forename: Roderick N
authors.initials: RN
authors.lastname: Carter
authors.affiliation: Molecular Metabolism Group, University/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburg, EH16 4TJ, UK.
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Morton
authors.affiliation: MRC Centre for Regenerative Medicine, Institute for Stem Cell Research, The University of Edinburgh, Edinburgh, EH16 4UU, UK.
authors.forename: Fella
authors.initials: F
authors.lastname: Hammachi
authors.affiliation: MRC Centre for Regenerative Medicine, Institute for Stem Cell Research, The University of Edinburgh, Edinburgh, EH16 4UU, UK.
authors.forename: Tilo
authors.initials: T
authors.lastname: Kunath
authors.affiliation: Centre for Integrative Physiology, University of Edinburgh, Hugh Robson Building, Edinburgh, EH8 9XD, UK.|Euan MacDonald Centre for Motor Neurone Disease Research, Chancellor's Building, University of Edinburgh, Edinburgh, EH16 4SB, UK.
authors.forename: Giuseppa
authors.initials: G
authors.lastname: Pennetta
authors.affiliation: Division of Neurobiology, The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Edinburgh, EH25 9RG, UK.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Carpanini
authors.affiliation: Division of Neurobiology, The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Edinburgh, EH25 9RG, UK.
authors.forename: Jean C
authors.initials: JC
authors.lastname: Manson
authors.affiliation: FingerPrints Proteomics Facility, College of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK.
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Lamont
authors.affiliation: Euan MacDonald Centre for Motor Neurone Disease Research, Chancellor's Building, University of Edinburgh, Edinburgh, EH16 4SB, UK.|Division of Neurobiology, The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Edinburgh, EH25 9RG, UK.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Wishart
authors.affiliation: Centre for Integrative Physiology, University of Edinburgh, Hugh Robson Building, Edinburgh, EH8 9XD, UK T.Gillingwater@ed.ac.uk.|Euan MacDonald Centre for Motor Neurone Disease Research, Chancellor's Building, University of Edinburgh, Edinburgh, EH16 4SB, UK.
authors.forename: Thomas H
authors.identifier: 0000-0002-0306-5577
authors.initials: TH
authors.lastname: Gillingwater
mesh_terms: D000818:Animals; D027682:Cation Transport Proteins / Q000378:metabolism*; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000378:metabolism; D004734:Energy Metabolism; D063990:Gene Ontology; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051336:Mitochondrial Membranes / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism*; D009469:Neuromuscular Junction / Q000378:metabolism; D013569:Synapses / Q000378:metabolism*; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D027682:Cation Transport Proteins; D029721:Drosophila Proteins; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; C000621798:Sfxn2 protein, Drosophila; C506522:Sfxn3 protein, mouse; D051844:alpha-Synuclein
keywords: Alpha-synuclein; Mitochondria; Neurodegeneration; Sideroflexin 3; Synapse