ABSTRACT
OBJECTIVE: Whereas the contribution of α-synuclein to neurodegeneration in Parkinson disease is well accepted, the putative impact of its close homologue, ß-synuclein, is enigmatic. ß-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 ß-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 ß-synuclein linked to dementia with Lewy bodies rendered the protein neurotoxic in transgenic mice, and fibrillation of ß-synuclein has been demonstrated in vitro. METHODS: Neurotoxicity and aggregation properties of α-, ß-, and γ-synuclein were comparatively elucidated in the rat nigro-striatal projection and in cultured neurons. RESULTS: Supporting the hypothesis that ß-synuclein can act as a neurodegeneration-inducing factor, we demonstrated that wild-type ß-synuclein is neurotoxic for cultured primary neurons. Furthermore, ß-synuclein formed proteinase K-resistant aggregates in dopaminergic neurons in vivo, leading to pronounced and progressive neurodegeneration in rats. Expression of ß-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-, ß-, and γ-synuclein revealed that ß-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 ß-synuclein as a putative modulator of neuropathology in aggregopathies like Parkinson disease and dementia with Lewy bodies needs to be revisited.
