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β-synuclein aggregates and induces neurodegeneration in dopaminergic neurons

Authors

  • Grit Taschenberger PhD,

    1. Department of Neurology, Center for Nanoscale Microscopy and Molecular Physiology of the Brain at University Medical Center Göttingen, Göttingen, Germany
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  • Johan Toloe PhD,

    1. Department of Neurology, Center for Nanoscale Microscopy and Molecular Physiology of the Brain at University Medical Center Göttingen, Göttingen, Germany
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  • Julia Tereshchenko PhD,

    1. Department of Neurology, Center for Nanoscale Microscopy and Molecular Physiology of the Brain at University Medical Center Göttingen, Göttingen, Germany
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  • Jasper Akerboom PhD,

    1. Janelia Farm Research Campus, Howard Hughes Medical Institute, Ashburn, VA
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  • Pauline Wales PhD,

    1. Department of Neurodegeneration and Restorative Research, University Medical Center Göttingen, Göttingen, Germany
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  • Roland Benz PhD,

    1. Rudolf Virchow Center, DFG Research Center for Experimental Biomedicine, University of Würzburg, Würzburg, Germany
    2. School of Engineering and Science, Jacobs University Bremen, Bremen, Germany
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  • Stefan Becker PhD,

    1. Max Plank Institute for Biophysical Chemistry, Göttingen, Germany
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  • Tiago F. Outeiro PhD,

    1. Department of Neurodegeneration and Restorative Research, University Medical Center Göttingen, Göttingen, Germany
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  • Loren L. Looger PhD,

    1. Janelia Farm Research Campus, Howard Hughes Medical Institute, Ashburn, VA
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  • Mathias Bähr MD,

    1. Department of Neurology, Center for Nanoscale Microscopy and Molecular Physiology of the Brain at University Medical Center Göttingen, Göttingen, Germany
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  • Markus Zweckstetter PhD,

    1. Max Plank Institute for Biophysical Chemistry, Göttingen, Germany
    2. Center for Neurodegenerative Diseases, Göttingen, Germany
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  • Sebastian Kügler PhD

    Corresponding author
    • Department of Neurology, Center for Nanoscale Microscopy and Molecular Physiology of the Brain at University Medical Center Göttingen, Göttingen, Germany
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Address correspondence to Dr Kügler, University Medical Center Göttingen, Department of Neurology, Waldweg 33, 37073 Göttingen, Germany. E-mail: sebastian.kuegler@med.uni-goettingen.de

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. Ann Neurol 2013;74:109–118

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