title: Activation of Mitochondrial Complex II-Dependent Respiration Is Beneficial for α-Synucleinopathies.
abstract: Parkinson's disease and dementia with Lewy bodies are major challenges in research and clinical medicine world-wide and contribute to the most common neurodegenerative disorders. Previously, specific mitochondrial polymorphisms have been found to enhance clearance of amyloid-β from the brain of APP-transgenic mice leading to beneficial clinical outcome. It has been discussed whether specific mitochondrial alterations contribute to disease progression or even prevent toxic peptide deposition, as seen in many neurodegenerative diseases. Here, we investigated α-synuclein-transgenic C57BL/6J mice with the A30P mutation, and a novel A30P C57BL/6J mouse model with three mitochondrial DNA polymorphisms in the ND3, COX3 and mtRNA(Arg) genes, as found in the inbred NOD/LtJ mouse strain. We were able to detect that the new model has increased mitochondrial complex II-respiration which occurs in parallel to neuronal loss and improved motor performance, although it exhibits higher amounts of high molecular weight species of α-synuclein. High molecular weight aggregates of different peptides are controversially discussed in the light of neurodegeneration. A favourable hypothesis states that high molecular weight species are protective and of minor importance for the pathogenesis of neurodegenerative disorders as compared to the extreme neurotoxic monomers and oligomers. Summarising, our results point to a potentially protective and beneficial effect of specific mitochondrial polymorphisms which cause improved mitochondrial complex II-respiration in α-synucleinopathies, an effect that could be exploited further for pharmaceutical interventions.
authors: Department of Neurology, Neurodegeneration Research Lab (NRL), University of Magdeburg, Magdeburg, Germany.
authors: Christina
authors: C
authors: Fröhlich
authors: Department of Neurology, Neurodegeneration Research Lab (NRL), University of Magdeburg, Magdeburg, Germany.|University of Frankfurt, Institute of Clinical Pharmacology/ZAFES, Frankfurt, Germany.
authors: Katja
authors: K
authors: Zschiebsch
authors: Department of Neurology, Neurodegeneration Research Lab (NRL), University of Magdeburg, Magdeburg, Germany.|Fraunhofer Institute for Cell Therapy and Immunology (IZI), Halle, Germany.
authors: Victoria
authors: V
authors: Gröger
authors: Department of Pathology (PAT), Translational Neurodegeneration Research and Neuropathology Lab, University of Oslo (UiO) and Oslo University Hospital (OUS), Postboks 4950 Nydalen, 0424, Oslo, Norway.|Department of Neurology, Neurodegeneration Research Lab (NRL), University of Magdeburg, Magdeburg, Germany.|LIED, University of Lübeck (UzL), Lübeck, Germany.
authors: Kristin
authors: K
authors: Paarmann
authors: Department of Pathology (PAT), Translational Neurodegeneration Research and Neuropathology Lab, University of Oslo (UiO) and Oslo University Hospital (OUS), Postboks 4950 Nydalen, 0424, Oslo, Norway.|Department of Neurology, Neurodegeneration Research Lab (NRL), University of Magdeburg, Magdeburg, Germany.|LIED, University of Lübeck (UzL), Lübeck, Germany.
authors: Johannes
authors: J
authors: Steffen
authors: Department of Neurology, Neurodegeneration Research Lab (NRL), University of Magdeburg, Magdeburg, Germany.
authors: Christoph
authors: C
authors: Thurm
authors: Department of Neurology, Neurodegeneration Research Lab (NRL), University of Magdeburg, Magdeburg, Germany.
authors: Eva-Maria
authors: EM
authors: Schropp
authors: Department of Pathology (PAT), Translational Neurodegeneration Research and Neuropathology Lab, University of Oslo (UiO) and Oslo University Hospital (OUS), Postboks 4950 Nydalen, 0424, Oslo, Norway.|Department of Neurology, Neurodegeneration Research Lab (NRL), University of Magdeburg, Magdeburg, Germany.
authors: Thomas
authors: T
authors: Brüning
authors: Department of Neurology, University of Magdeburg/Leibniz Institut for Neurobiology, Magdeburg, Germany.
authors: Frank
authors: F
authors: Gellerich
authors: Institute for Mathematical Stochastics, University of Magdeburg, Magdeburg, Germany.
authors: Martin
authors: M
authors: Radloff
authors: Institute for Mathematical Stochastics, University of Magdeburg, Magdeburg, Germany.
authors: Rainer
authors: R
authors: Schwabe
authors: AJ Roboscreen GmbH, Leipzig, Germany.
authors: Ingolf
authors: I
authors: Lachmann
authors: Department of Pathology (PAT), Translational Neurodegeneration Research and Neuropathology Lab, University of Oslo (UiO) and Oslo University Hospital (OUS), Postboks 4950 Nydalen, 0424, Oslo, Norway.|Department of Neurology, Neurodegeneration Research Lab (NRL), University of Magdeburg, Magdeburg, Germany.
authors: Markus
authors: M
authors: Krohn
authors: LIED, University of Lübeck (UzL), Lübeck, Germany.
authors: Saleh
authors: S
authors: Ibrahim
authors: Department of Pathology (PAT), Translational Neurodegeneration Research and Neuropathology Lab, University of Oslo (UiO) and Oslo University Hospital (OUS), Postboks 4950 Nydalen, 0424, Oslo, Norway. jens.pahnke@medisin.uio.no.|Department of Neurology, Neurodegeneration Research Lab (NRL), University of Magdeburg, Magdeburg, Germany. jens.pahnke@medisin.uio.no.|LIED, University of Lübeck (UzL), Lübeck, Germany. jens.pahnke@medisin.uio.no.|Department of Bioorganic Chemistry, Leibniz-Institute of Plant Biochemistry (IPB), Halle, Germany. jens.pahnke@medisin.uio.no.
authors: Jens
authors: J
authors: Pahnke
mesh_terms: D000818:Animals; D019069:Cell Respiration / Q000502:physiology; D042963:Electron Transport Complex II / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: D051844:alpha-Synuclein; D042963:Electron Transport Complex II
keywords: Alpha-synuclein; Complex II; Mitochondria; Oxidative phosphorylation; Parkinson’s disease