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

The pre-synaptic protein a-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 a-synuclein gene cause familial forms of Parkinson’s disease and dementia with Lewy bodies. We previously described a transgenic mouse line expressing truncated human a-synuclein(1-120) that develops a-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 a-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 a-synuclein(1–140) or truncated a-synuclein(1-120) was reduced. These findings reveal a novel gain of toxic function of a-synuclein at the synapse, which may be an early event in the pathogenesis of Parkinson’s disease.