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.
Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 0PY, UK.
Pablo
P
Garcia-Reitböck
Oleg
O
Anichtchik
Arianna
A
Bellucci
Mariangela
M
Iovino
Chiara
C
Ballini
Elena
E
Fineberg
Bernardino
B
Ghetti
Laura
L
Della Corte
PierFranco
P
Spano
George K
GK
Tofaris
Michel
M
Goedert
Maria Grazia
MG
Spillantini
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