SNARE protein redistribution and synaptic failure in a transgenic mouse model of Parkinson's disease.
The pre-synaptic protein alpha-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 alpha-synuclein gene cause familial forms of Parkinson's disease and dementia with Lewy bodies. We previously described a transgenic mouse line expressing truncated human alpha-synuclein(1-120) that develops alpha-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 alpha-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 alpha-synuclein(1-140) or truncated alpha-synuclein(1-120) was reduced. These findings reveal a novel gain of toxic function of alpha-synuclein at the synapse, which may be an early event in the pathogenesis of Parkinson's disease.
Garcia-Reitböck
Pablo
P
Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 0PY, UK.
Anichtchik
Oleg
O
Bellucci
Arianna
A
Iovino
Mariangela
M
Ballini
Chiara
C
Fineberg
Elena
E
Ghetti
Bernardino
B
Della Corte
Laura
L
Spano
PierFranco
P
Tofaris
George K
GK
Goedert
Michel
M
Spillantini
Maria Grazia
MG
D000368:Aged; D000818:Animals; D004195:Disease Models, Animal; D005089:Exocytosis / Q000235:genetics; D006801:Humans; D007223:Infant; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology*; D050600:SNARE Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D013569:Synapses / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051844:alpha-Synuclein / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology
D050600:SNARE Proteins; D051844:alpha-Synuclein