Document Detail


β-synuclein aggregates and induces neurodegeneration in dopaminergic neurons.
MedLine Citation:
PMID:  23536356     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Grit Taschenberger; Johan Toloe; Julia Tereshchenko; Jasper Akerboom; Pauline Wales; Roland Benz; Stefan Becker; Tiago F Outeiro; Loren L Looger; Mathias Bähr; Markus Zweckstetter; Sebastian Kügler
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2013-08-06
Journal Detail:
Title:  Annals of neurology     Volume:  74     ISSN:  1531-8249     ISO Abbreviation:  Ann. Neurol.     Publication Date:  2013 Jul 
Date Detail:
Created Date:  2013-09-16     Completed Date:  2013-11-07     Revised Date:  2014-07-14    
Medline Journal Info:
Nlm Unique ID:  7707449     Medline TA:  Ann Neurol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  109-18     Citation Subset:  IM    
Copyright Information:
© 2013 American Neurological Association.
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MeSH Terms
Descriptor/Qualifier:
Animals
Biophysical Processes / drug effects,  genetics
Calcium / metabolism
Cells, Cultured
Dependovirus / physiology
Dopaminergic Neurons / metabolism*,  ultrastructure
Embryo, Mammalian
Female
Green Fluorescent Proteins / genetics,  metabolism
Membrane Potentials / drug effects
Microscopy, Electron, Transmission
Mitochondria / drug effects,  ultrastructure
Mutation / genetics
Nerve Degeneration / chemically induced*
Rats
Rats, Wistar
Respiration
Substantia Nigra / cytology
Transfection
Vesicular Monoamine Transport Proteins
alpha-Synuclein / genetics,  toxicity
beta-Synuclein / genetics,  metabolism*
gamma-Synuclein / genetics,  metabolism
Chemical
Reg. No./Substance:
0/Slc18a2 protein, rat; 0/Vesicular Monoamine Transport Proteins; 0/alpha-Synuclein; 0/beta-Synuclein; 0/enhanced green fluorescent protein; 0/gamma-Synuclein; 147336-22-9/Green Fluorescent Proteins; SY7Q814VUP/Calcium
Comments/Corrections
Comment In:
Ann Neurol. 2013 Aug;74(2):306-7   [PMID:  24022909 ]
Ann Neurol. 2013 Aug;74(2):306   [PMID:  23836414 ]

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