[beta]-synuclein aggregates and induces neurodegeneration in dopaminergic neurons

• Published in: Annals of neurology 2013-07, Vol.74 (1), p.109-118
• Main Authors: Taschenberger, Grit, Toloe, Johan, Tereshchenko, Julia, Akerboom, Jasper, Wales, Pauline, Benz, Roland, Becker, Stefan, Outeiro, Tiago F, Looger, Loren L, Bähr, Mathias, Zweckstetter, Markus, Kugler, Sebastian
• Format: Article
• Language: English
• Subjects: Beta; Neurodegeneration; Neurons; Neurotoxicity; Parkinson's disease
• ISSN: 0364-5134; 1531-8249
• DOI: 10.1002/ana.23905

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