Pathological changes in dopaminergic nerve cells of the substantia nigra and olfactory bulb in mice transgenic for truncated human alpha-synuclein(1-120): implications for Lewy body disorders.
Dysfunction of the 140 aa protein alpha-synuclein plays a central role in Lewy body disorders, including Parkinson's disease, as well as in multiple system atrophy. Here, we show that the expression of truncated human alpha-synuclein(1-120), driven by the rat tyrosine hydroxylase promoter on a mouse alpha-synuclein null background, leads to the formation of pathological inclusions in the substantia nigra and olfactory bulb and to a reduction in striatal dopamine levels. At the behavioral level, the transgenic mice showed a progressive reduction in spontaneous locomotion and an increased response to amphetamine. These findings suggest that the C-terminal of alpha-synuclein is an important regulator of aggregation in vivo and will help to understand the mechanisms underlying the pathogenesis of Lewy body disorders and multiple system atrophy.
Tofaris
George K
GK
Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 2PY, United Kingdom.
Garcia Reitböck
Pablo
P
Humby
Trevor
T
Lambourne
Sarah L
SL
O'Connell
Mark
M
Ghetti
Bernardino
B
Gossage
Helen
H
Emson
Piers C
PC
Wilkinson
Lawrence S
LS
Goedert
Michel
M
Spillantini
Maria Grazia
MG
D000818:Animals; D004298:Dopamine / Q000502:physiology*; D006801:Humans; D016631:Lewy Bodies / Q000473:pathology*; D020961:Lewy Body Disease / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D009474:Neurons / Q000473:pathology*; D009830:Olfactory Bulb / Q000473:pathology*; D010300:Parkinson Disease / Q000235:genetics / Q000473:pathology; D011401:Promoter Regions, Genetic; D051381:Rats; D013378:Substantia Nigra / Q000473:pathology*; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics; D051844:alpha-Synuclein / Q000235:genetics*
D051844:alpha-Synuclein; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine