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Front. Mol. Neurosci. | doi: 10.3389/fnmol.2018.00049

Pathophysiological consequences of neuronal α-Synuclein overexpression: impacts on ion homeostasis, stress signalling, mitochondrial integrity and electrical activity

 Johan Toloe1,  Grit Taschenberger1,  Kristian Leite1, Markus Stahlberg2, Gesche Spelbrink1, Janina Kues1, Francesca Munari3,  Stefano Capaldi4, Stefan Becker5, Markus Zweckstetter3,  Camin Dean2,  Mathias Bahr1 and  Sebastian Kügler1*
  • 1Dept. of Neurology, University Medicine Göttingen, Germany
  • 2European Neuroscience Institute, University of Göttingen, Germany
  • 3German Center for Neurodegenerative Diseases (DZNE), Germany
  • 4Dept. of Biotechnology, Biochristallography Laboratory, University of Verona, Italy
  • 5Dept. for NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, Germany

α-Synuclein (α-Syn) is intimately linked to the aetiology of Parkinson´s Disease, as mutations and even subtle increases in gene dosage result in early onset of the disease.
However, how this protein causes neuronal dysfunction and neurodegeneration is incompletely understood. We thus examined a comprehensive range of physiological parameters in cultured rat primary neurons overexpressing α-Syn at levels causing a slowly progressive neurodegeneration. In contradiction to earlier reports from non-neuronal assay systems we demonstrate that α-Syn does not interfere with essential ion handling capacities, mitochondrial capability of ATP production or basic electro-physiological properties like resting membrane potential or the general ability to generate action potentials. α-Syn also does not activate canonical stress kinase signalling converging on SAPK/Jun, p38 MAPK or Erk kinases. Causative for α-Syn-induced neurodegeneration are mitochondrial thiol oxidation and activation of caspases downstream of mitochondrial outer membrane permeabilization, leading to apoptosis-like cell death execution with some unusual aspects.
We also aimed to elucidate neuroprotective strategies counteracting the pathophysiological processes caused by α-Syn. Neurotrophic factors, calpain inhibition and increased lysosomal protease capacity showed no protective effects against α-Syn overexpression. In contrast, the major watchdog of outer mitochondrial membrane integrity, Bcl-Xl, was capable of almost completely preventing neuron death, but did not prevent mitochondrial thiol oxidation. Importantly, independent from the quite mono-causal induction of neurotoxicity, α-Syn causes diminished excitability of neurons by external stimuli and robust impairments in endogenous neuronal network activity by decreasing the frequency of action potentials generated without external stimulation. This latter finding suggests that α-Syn can induce neuronal dysfunction independent from its induction of neurotoxicity and might serve as an explanation for functional deficits that precede neuronal cell loss in synucleopathies like Parkinson´s disease or dementia with Lewy bodies.

Keywords: Synucleins, Atp production, calcium homeostasis, Reactive Oxygen Species, Thiol oxidation, Apaptosis, Bcl-XL, Neuronal network activity

Received: 01 Nov 2017; Accepted: 06 Feb 2018.

Edited by:

Andrei Surguchov, University of Kansas Medical Center, United States

Reviewed by:

Carsten Culmsee, Philipps University of Marburg, Germany
Fatemeh Nouri Emamzadeh, United States Food and Drug Administration, United States  

Copyright: © 2018 Toloe, Taschenberger, Leite, Stahlberg, Spelbrink, Kues, Munari, Capaldi, Becker, Zweckstetter, Dean, Bahr and Kügler. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Sebastian Kügler, University Medicine Göttingen, Dept. of Neurology, Waldweg 33, Göttingen, 37073, Germany,