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  Beta-synuclein aggregates and induces neurodegeneration in dopaminergic neurons.

Taschenberger, G., Toloe, J., Tereshchenko, J., Akerboom, J., Wales, P., Benz, R., et al. (2013). Beta-synuclein aggregates and induces neurodegeneration in dopaminergic neurons. Annals of Neurology, 74(1), 109-118. doi:10.1002/ana.23905.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0015-36E3-B Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0028-E5D2-4
Genre: Journal Article

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Taschenberger, G., Author
Toloe, J., Author
Tereshchenko, J., Author
Akerboom, J., Author
Wales, P., Author
Benz, R., Author
Becker, S.1, Author              
Outeiro, T. F., Author
Looger, L. L., Author
Bähr, M., Author
Zweckstetter, M.2, Author              
Kügler, S., Author
Affiliations:
1Department of NMR Based Structural Biology, MPI for biophysical chemistry, Max Planck Society, ou_578567              
2Research Group of Protein Structure Determination using NMR, MPI for biophysical chemistry, Max Planck Society, ou_578571              

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 Abstract: Objective: Whereas the contribution of α-synuclein to neurodegeneration in Parkinson disease is well accepted, the putative impact of its close homologue, β-synuclein, is enigmatic. β-Synuclein is widely expressed throughout the central nervous system, as is α-synuclein, but the physiological functions of both proteins remain unknown. Recent findings have supported the view that β-synuclein can act as an ameliorating regulator of α-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 β-synuclein linked to dementia with Lewy bodies rendered the protein neurotoxic in transgenic mice, and fibrillation of β-synuclein has been demonstrated in vitro. Methods: Neurotoxicity and aggregation properties of α-, β-, and γ-synuclein were comparatively elucidated in the rat nigro-striatal projection and in cultured neurons. Results: Supporting the hypothesis that β-synuclein can act as a neurodegeneration-inducing factor, we demonstrated that wild-type β-synuclein is neurotoxic for cultured primary neurons. Furthermore, β-synuclein formed proteinase K–resistant aggregates in dopaminergic neurons in vivo, leading to pronounced and progressive neurodegeneration in rats. Expression of β-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 α-, β-, and γ-synuclein revealed that β-synuclein was eventually as neurotoxic as α-synuclein for nigral dopaminergic neurons, whereas γ-synuclein proved to be nontoxic and had very low aggregation propensity. Interpretation: Our results suggest that the role of β-synuclein as a putative modulator of neuropathology in aggregopathies like Parkinson disease and dementia with Lewy bodies needs to be revisited.

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Language(s): eng - English
 Dates: 2013-08-06
 Publication Status: Published online
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 Rev. Method: Peer
 Identifiers: DOI: 10.1002/ana.23905
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Title: Annals of Neurology
Source Genre: Journal
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Pages: - Volume / Issue: 74 (1) Sequence Number: - Start / End Page: 109 - 118 Identifier: -