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Tönges L, Szegö EM, Hause P, et al. Alpha-synuclein mutations impair axonal regeneration in models of Parkinson's disease. Front Aging Neurosci. 2014;6:239doi: 10.3389/fnagi.2014.00239.
Tönges, L., Szegö, E. M., Hause, P., Saal, K. A., Tatenhorst, L., Koch, J. C., D Hedouville, Z., Dambeck, V., Kügler, S., Dohm, C. P., Bähr, M., & Lingor, P. (2014). Alpha-synuclein mutations impair axonal regeneration in models of Parkinson's disease. Frontiers in aging neuroscience, 6239. https://doi.org/10.3389/fnagi.2014.00239
Tönges, Lars, et al. "Alpha-synuclein mutations impair axonal regeneration in models of Parkinson's disease." Frontiers in aging neuroscience vol. 6 (2014): 239. doi: https://doi.org/10.3389/fnagi.2014.00239
Tönges L, Szegö EM, Hause P, Saal KA, Tatenhorst L, Koch JC, D Hedouville Z, Dambeck V, Kügler S, Dohm CP, Bähr M, Lingor P. Alpha-synuclein mutations impair axonal regeneration in models of Parkinson's disease. Front Aging Neurosci. 2014 Sep 10;6:239. doi: 10.3389/fnagi.2014.00239. eCollection 2014. PMID: 25309425; PMCID: PMC4159996.
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Front Aging Neurosci. 2014 Sep 10;6:239. doi: 10.3389/fnagi.2014.00239. eCollection 2014.

Alpha-synuclein mutations impair axonal regeneration in models of Parkinson's disease.

Frontiers in aging neuroscience

Lars Tönges, Eva M Szegö, Patrizia Hause, Kim-Ann Saal, Lars Tatenhorst, Jan Christoph Koch, Zara D Hedouville, Vivian Dambeck, Sebastian Kügler, Christoph P Dohm, Mathias Bähr, Paul Lingor

Affiliations

  1. Department of Neurology, University Medicine Göttingen Göttingen, Germany ; Nanoscale Microscopy and Molecular Physiology of the Brain, Cluster of Excellence 171-DFG Research Center 103 (CNMPB) Göttingen, Germany.
  2. Department of Neurodegeneration and Restorative Research, University Medicine Göttingen Göttingen, Germany.
  3. Department of Neurology, University Medicine Göttingen Göttingen, Germany.

PMID: 25309425 PMCID: PMC4159996 DOI: 10.3389/fnagi.2014.00239

Abstract

The dopaminergic (DAergic) nigrostriatal tract has an intrinsic regenerative capacity which can be impaired in Parkinson's disease (PD). Alpha-synuclein (aSyn) is a major pathogenic component in PD but its impact on DAergic axonal regeneration is largely unknown. In this study, we expressed pathogenic variants of human aSyn by means of recombinant adeno-associated viral vectors in experimental paradigms of DAergic regeneration. In a scratch lesion model in vitro, both aSyn(A30P) and aSyn(A53T) significantly reduced DAergic neurite regeneration and induced loss of TH-immunopositive cells while aSyn(WT) showed only minor cellular neurotoxic effects. The striatal density of TH-immunopositive axons in the striatal 6-OHDA lesion mouse model was attenuated only by aSyn(A30P). However, striatal expression levels of the regeneration marker GAP-43 in TH-immunopositive fibers were reduced by both aSyn(A30P) and aSyn(A53T), but not by aSyn(WT), which was associated with an activation of the ROCK signaling pathway. Nigral DAergic cell loss was only mildly enhanced by additional overexpression of aSyn variants. Our findings indicate that mutations of aSyn have a strong impact on the regenerative capacity of DAergic neurons, which may contribute to their pathogenic effects.

Keywords: 6-OHDA; A30P; A53T; GAP-43; ROCK; alpha-synuclein; axonal regeneration; dopaminergic cell death

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