SNARE protein redistribution and synaptic failure in a transgenic mouse model of Parkinson's disease

Pablo Garcia-Reitböck, Oleg Anichtchik, Arianna Bellucci, Mariangela Iovino, Chiara Ballini, Elena Fineberg, Bernardino Ghetti, Laura Della Corte, Pierfranco Spano, George K. Tofaris, Michel Goedert, Maria Grazia Spillantini

Research output: Contribution to journalArticle

Abstract

The pre-synaptic protein α-synuclein is the main component of Lewy bodies and Lewy neurites, the defining neuropathological characteristics of Parkinson's disease and dementia with Lewy bodies. Mutations in the α-synuclein gene cause familial forms of Parkinson's disease and dementia with Lewy bodies. We previously described a transgenic mouse line expressing truncated human α-synuclein(1-120) that develops α-synuclein aggregates, striatal dopamine deficiency and reduced locomotion, similar to Parkinson's disease. We now show that in the striatum of these mice, as in Parkinson's disease, synaptic accumulation of α-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 α-synuclein(1-140) or truncated α-synuclein(1-120) was reduced. These findings reveal a novel gain of toxic function of α-synuclein at the synapse, which may be an early event in the pathogenesis of Parkinson's disease.

Original languageEnglish
Pages (from-to)2032-2044
Number of pages13
JournalBrain
Volume133
Issue number7
DOIs
Publication statusPublished - Jul 2010

Keywords

  • alpha-synuclein
  • dopamine
  • neurodegenerative diseases
  • Parkinson's disease
  • SNARE proteins

ASJC Scopus subject areas

  • Clinical Neurology

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    Garcia-Reitböck, P., Anichtchik, O., Bellucci, A., Iovino, M., Ballini, C., Fineberg, E., Ghetti, B., Della Corte, L., Spano, P., Tofaris, G. K., Goedert, M., & Spillantini, M. G. (2010). SNARE protein redistribution and synaptic failure in a transgenic mouse model of Parkinson's disease. Brain, 133(7), 2032-2044. https://doi.org/10.1093/brain/awq132