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

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

Mol Neurobiol. 2016 Sep;53(7):4728-44

Authors: Fröhlich C, Zschiebsch K, Gröger V, Paarmann K, Steffen J, Thurm C, Schropp EM, Brüning T, Gellerich F, Radloff M, Schwabe R, Lachmann I, Krohn M, Ibrahim S, Pahnke J

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.

PMID: 26319560 [PubMed - in process]

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