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SNARE protein redistribution and synaptic failure in a transgenic mouse model of Parkinsons disease

SNARE protein redistribution and synaptic failure in a transgenic mouse model of Parkinsons disease The pre-synaptic protein -synuclein is the main component of Lewy bodies and Lewy neurites, the defining neuropathological characteristics of Parkinsons disease and dementia with Lewy bodies. Mutations in the -synuclein gene cause familial forms of Parkinsons disease and dementia with Lewy bodies. We previously described a transgenic mouse line expressing truncated human -synuclein(1-120) that develops -synuclein aggregates, striatal dopamine deficiency and reduced locomotion, similar to Parkinsons disease. We now show that in the striatum of these mice, as in Parkinsons disease, synaptic accumulation of -synuclein is accompanied by an age-dependent redistribution of the synaptic SNARE proteins SNAP-25, syntaxin-1 and synaptobrevin-2, as well as by an age-dependent reduction in dopamine release. Furthermore, the release of FM1-43 dye from PC12 cells expressing either human full-length -synuclein(1140) or truncated -synuclein(1-120) was reduced. These findings reveal a novel gain of toxic function of -synuclein at the synapse, which may be an early event in the pathogenesis of Parkinsons disease. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Brain Oxford University Press

SNARE protein redistribution and synaptic failure in a transgenic mouse model of Parkinsons disease

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References (55)

Publisher
Oxford University Press
Copyright
The Author (2010). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: [email protected]
ISSN
0006-8950
eISSN
1460-2156
DOI
10.1093/brain/awq132
pmid
20534649
Publisher site
See Article on Publisher Site

Abstract

The pre-synaptic protein -synuclein is the main component of Lewy bodies and Lewy neurites, the defining neuropathological characteristics of Parkinsons disease and dementia with Lewy bodies. Mutations in the -synuclein gene cause familial forms of Parkinsons disease and dementia with Lewy bodies. We previously described a transgenic mouse line expressing truncated human -synuclein(1-120) that develops -synuclein aggregates, striatal dopamine deficiency and reduced locomotion, similar to Parkinsons disease. We now show that in the striatum of these mice, as in Parkinsons disease, synaptic accumulation of -synuclein is accompanied by an age-dependent redistribution of the synaptic SNARE proteins SNAP-25, syntaxin-1 and synaptobrevin-2, as well as by an age-dependent reduction in dopamine release. Furthermore, the release of FM1-43 dye from PC12 cells expressing either human full-length -synuclein(1140) or truncated -synuclein(1-120) was reduced. These findings reveal a novel gain of toxic function of -synuclein at the synapse, which may be an early event in the pathogenesis of Parkinsons disease.

Journal

Brain – Oxford University Press

Published: Jul 9, 2010

Keywords: SNARE proteins Parkinson’s disease alpha-synuclein dopamine neurodegenerative diseases

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