title: β-synuclein aggregates and induces neurodegeneration in dopaminergic neurons.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Neurology, Center for Nanoscale Microscopy and Molecular Physiology of the Brain at University Medical Center Göttingen, Göttingen, Germany.
authors.forename: Grit
authors.initials: G
authors.lastname: Taschenberger
authors.forename: Johan
authors.initials: J
authors.lastname: Toloe
authors.forename: Julia
authors.initials: J
authors.lastname: Tereshchenko
authors.forename: Jasper
authors.initials: J
authors.lastname: Akerboom
authors.forename: Pauline
authors.initials: P
authors.lastname: Wales
authors.forename: Roland
authors.initials: R
authors.lastname: Benz
authors.forename: Stefan
authors.initials: S
authors.lastname: Becker
authors.forename: Tiago F
authors.initials: TF
authors.lastname: Outeiro
authors.forename: Loren L
authors.initials: LL
authors.lastname: Looger
authors.forename: Mathias
authors.initials: M
authors.lastname: Bähr
authors.forename: Markus
authors.initials: M
authors.lastname: Zweckstetter
authors.forename: Sebastian
authors.initials: S
authors.lastname: Kügler
mesh_terms: D000818:Animals; D055592:Biophysical Phenomena / Q000187:drug effects / Q000235:genetics; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D000229:Dependovirus / Q000502:physiology; D059290:Dopaminergic Neurons / Q000378:metabolism* / Q000648:ultrastructure; D004622:Embryo, Mammalian; D005260:Female; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000187:drug effects / Q000648:ultrastructure; D009154:Mutation / Q000235:genetics; D009410:Nerve Degeneration / Q000139:chemically induced*; D051381:Rats; D017208:Rats, Wistar; D012119:Respiration; D013378:Substantia Nigra / Q000166:cytology; D014162:Transfection; D050493:Vesicular Monoamine Transport Proteins; D051844:alpha-Synuclein / Q000235:genetics / Q000633:toxicity; D051846:beta-Synuclein / Q000235:genetics / Q000378:metabolism*; D051845:gamma-Synuclein / Q000235:genetics / Q000378:metabolism
chemical_list: C493454:Slc18a2 protein, rat; D050493:Vesicular Monoamine Transport Proteins; D051844:alpha-Synuclein; D051846:beta-Synuclein; C485184:enhanced green fluorescent protein; D051845:gamma-Synuclein; D049452:Green Fluorescent Proteins; D002118:Calcium