title: Monomeric Alpha-Synuclein Exerts a Physiological Role on Brain ATP Synthase.
abstract: Misfolded α-synuclein is a key factor in the pathogenesis of Parkinson's disease (PD). However, knowledge about a physiological role for the native, unfolded α-synuclein is limited. Using brains of mice lacking α-, β-, and γ-synuclein, we report that extracellular monomeric α-synuclein enters neurons and localizes to mitochondria, interacts with ATP synthase subunit α, and modulates ATP synthase function. Using a combination of biochemical, live-cell imaging and mitochondrial respiration analysis, we found that brain mitochondria of α-, β-, and γ-synuclein knock-out mice are uncoupled, as characterized by increased mitochondrial respiration and reduced mitochondrial membrane potential. Furthermore, synuclein deficiency results in reduced ATP synthase efficiency and lower ATP levels. Exogenous application of low unfolded α-synuclein concentrations is able to increase the ATP synthase activity that rescues the mitochondrial phenotypes observed in synuclein deficiency. Overall, the data suggest that α-synuclein is a previously unrecognized physiological regulator of mitochondrial bioenergetics through its ability to interact with ATP synthase and increase its efficiency. This may be of particular importance in times of stress or PD mutations leading to energy depletion and neuronal cell toxicity.
  
  
  
  Misfolded α-synuclein aggregations in the form of Lewy bodies have been shown to be a pathological hallmark in histological staining of Parkinson's disease (PD) patient brains. It is known that misfolded α-synuclein is a key driver in PD pathogenesis, but the physiological role of unfolded monomeric α-synuclein remains unclear. Using neuronal cocultures and isolated brain mitochondria of α-, β-, and γ-synuclein knock-out mice and monomeric α-synuclein, this current study shows that α-synuclein in its unfolded monomeric form improves ATP synthase efficiency and mitochondrial function. The ability of monomeric α-synuclein to enhance ATP synthase efficiency under physiological conditions may be of importance when α-synuclein undergoes the misfolding and aggregation reported in PD.
authors.affiliation: Department of Molecular Neuroscience, University College London Institute of Neurology, London WC1N 3BG, United Kingdom, and.
authors.forename: Marthe H R
authors.identifier: 0000-0003-1051-6425
authors.initials: MH
authors.lastname: Ludtmann
authors.affiliation: Department of Molecular Neuroscience, University College London Institute of Neurology, London WC1N 3BG, United Kingdom, and.
authors.forename: Plamena R
authors.initials: PR
authors.lastname: Angelova
authors.affiliation: School of Biosciences, University of Cardiff, Cardiff CF10 3AX, United Kingdom.
authors.forename: Natalia N
authors.identifier: 0000-0001-8570-5648
authors.initials: NN
authors.lastname: Ninkina
authors.affiliation: Department of Molecular Neuroscience, University College London Institute of Neurology, London WC1N 3BG, United Kingdom, and.
authors.forename: Sonia
authors.initials: S
authors.lastname: Gandhi
authors.affiliation: School of Biosciences, University of Cardiff, Cardiff CF10 3AX, United Kingdom a.abramov@ucl.ac.uk BuchmanVL@cardiff.ac.uk.
authors.forename: Vladimir L
authors.identifier: 0000-0002-7631-8352
authors.initials: VL
authors.lastname: Buchman
authors.affiliation: Department of Molecular Neuroscience, University College London Institute of Neurology, London WC1N 3BG, United Kingdom, and a.abramov@ucl.ac.uk BuchmanVL@cardiff.ac.uk.
authors.forename: Andrey Y
authors.identifier: 0000-0002-7646-7235
authors.initials: AY
authors.lastname: Abramov
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000201:enzymology / Q000378:metabolism; D001921:Brain / Q000201:enzymology*; D002478:Cells, Cultured; D004734:Energy Metabolism / Q000235:genetics / Q000502:physiology; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D025261:Mitochondrial Proton-Translocating ATPases / Q000378:metabolism*; D009243:NAD / Q000378:metabolism; D010101:Oxygen Consumption / Q000502:physiology; D056811:Unfolded Protein Response / Q000235:genetics; D051844:alpha-Synuclein / Q000235:genetics / Q000502:physiology*
chemical_list: C497605:Snca protein, mouse; D051844:alpha-Synuclein; D009243:NAD; D000255:Adenosine Triphosphate; D025261:Mitochondrial Proton-Translocating ATPases
keywords: ATP synthase; alpha-synuclein; astrocytes; bioenergetics; mitochondria; neurons