β-synuclein aggregates and induces neurodegeneration in dopaminergic neurons
Article first published online: 6 AUG 2013
© 2013 American Neurological Association
Annals of Neurology
Volume 74, Issue 1, pages 109–118, July 2013
How to Cite
Taschenberger, G., Toloe, J., Tereshchenko, J., Akerboom, J., Wales, P., Benz, R., Becker, S., Outeiro, T. F., Looger, L. L., Bähr, M., Zweckstetter, M. and Kügler, S. (2013), β-synuclein aggregates and induces neurodegeneration in dopaminergic neurons. Ann Neurol., 74: 109–118. doi: 10.1002/ana.23905
- Issue published online: 27 AUG 2013
- Article first published online: 6 AUG 2013
- Accepted manuscript online: 28 MAR 2013 03:36AM EST
- Manuscript Accepted: 22 MAR 2013
- Manuscript Revised: 7 MAR 2013
- Manuscript Received: 9 OCT 2012
- German Research Council–funded Center of Molecular Physiology of the Brain
- Bundesministerium für Bildung und Forschung. Grant Number: 01GS08190
- Marie Curie International Reintegration
- European Molecular Biology Organization installation
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.
Neurotoxicity and aggregation properties of α-, β-, and γ-synuclein were comparatively elucidated in the rat nigro-striatal projection and in cultured neurons.
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.
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