β-Synuclein Aggregates and Induces Neurodegeneration in Dopaminergic Neurons

2013 | journal article; research paper. A publication with affiliation to the University of Göttingen.

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​β-Synuclein Aggregates and Induces Neurodegeneration in Dopaminergic Neurons​
Taschenberger, G. ; Toloe, J. ; Tereshchenko, J. ; Akerboom, J.; Wales, P. ; Benz, R. & Becker, S.  et al.​ (2013) 
Annals of Neurology74(1) pp. 109​-118​.​ DOI: https://doi.org/10.1002/ana.23905 

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Authors
Taschenberger, G. ; Toloe, J. ; Tereshchenko, J. ; Akerboom, J.; Wales, P. ; Benz, R.; Becker, Stefan ; Outeiro, T. F. ; Looger, L. L.; Bähr, M. ; Zweckstetter, M. ; Kügler, Sebastian 
Abstract
ObjectiveWhereas the contribution of -synuclein to neurodegeneration in Parkinson disease is well accepted, the putative impact of its close homologue, -synuclein, is enigmatic. -Synuclein is widely expressed throughout the central nervous system, as is -synuclein, but the physiological functions of both proteins remain unknown. Recent findings have supported the view that -synuclein can act as an ameliorating regulator of -synuclein-induced neurotoxicity, having neuroprotective rather than neurodegenerative capabilities, and being nonaggregating due to the absence of most of the aggregation-promoting NAC domain. However, a mutation of -synuclein linked to dementia with Lewy bodies rendered the protein neurotoxic in transgenic mice, and fibrillation of -synuclein has been demonstrated in vitro. MethodsNeurotoxicity and aggregation properties of -, -, and -synuclein were comparatively elucidated in the rat nigro-striatal projection and in cultured neurons. ResultsSupporting the hypothesis that -synuclein can act as a neurodegeneration-inducing factor, we demonstrated that wild-type -synuclein is neurotoxic for cultured primary neurons. Furthermore, -synuclein formed proteinase K-resistant aggregates in dopaminergic neurons in vivo, leading to pronounced and progressive neurodegeneration in rats. Expression of -synuclein caused mitochondrial fragmentation, but this fragmentation did not render mitochondria nonfunctional in terms of ion handling and respiration even at late stages of neurodegeneration. A comparison of the neurodegenerative effects induced by -, -, and -synuclein revealed that -synuclein was eventually as neurotoxic as -synuclein for nigral dopaminergic neurons, whereas -synuclein proved to be nontoxic and had very low aggregation propensity. InterpretationOur results suggest that the role of -synuclein as a putative modulator of neuropathology in aggregopathies like Parkinson disease and dementia with Lewy bodies needs to be revisited. Ann Neurol 2013;74:109-118
Issue Date
2013
Journal
Annals of Neurology 
ISSN
0364-5134
eISSN
1531-8249
Language
English

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