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Mol Neurobiol. 2016 Sep;53(7):4728-44. doi: 10.1007/s12035-015-9399-4. Epub 2015 Aug 29.

Activation of Mitochondrial Complex II-Dependent Respiration Is Beneficial for α-Synucleinopathies.

Author information

1
Department of Neurology, Neurodegeneration Research Lab (NRL), University of Magdeburg, Magdeburg, Germany.
2
University of Frankfurt, Institute of Clinical Pharmacology/ZAFES, Frankfurt, Germany.
3
Fraunhofer Institute for Cell Therapy and Immunology (IZI), Halle, Germany.
4
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.
5
LIED, University of Lübeck (UzL), Lübeck, Germany.
6
Department of Neurology, University of Magdeburg/Leibniz Institut for Neurobiology, Magdeburg, Germany.
7
Institute for Mathematical Stochastics, University of Magdeburg, Magdeburg, Germany.
8
AJ Roboscreen GmbH, Leipzig, Germany.
9
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.
10
Department of Neurology, Neurodegeneration Research Lab (NRL), University of Magdeburg, Magdeburg, Germany. jens.pahnke@medisin.uio.no.
11
LIED, University of Lübeck (UzL), Lübeck, Germany. jens.pahnke@medisin.uio.no.
12
Department of Bioorganic Chemistry, Leibniz-Institute of Plant Biochemistry (IPB), Halle, Germany. jens.pahnke@medisin.uio.no.

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.

KEYWORDS:

Alpha-synuclein; Complex II; Mitochondria; Oxidative phosphorylation; Parkinson’s disease

PMID:
26319560
PMCID:
PMC4965489
DOI:
10.1007/s12035-015-9399-4
[Indexed for MEDLINE]
Free PMC Article

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