Lack of nigral pathology in transgenic mice expressing human alpha-synuclein driven by the tyrosine hydroxylase promoter.
alpha-Synuclein has been identified as a major component of Lewy body inclusions, which are one of the pathologic hallmarks of idiopathic Parkinson's disease. Mutations in alpha-synuclein have been found to be responsible for rare familial cases of Parkinsonism. To test whether overexpression of human alpha-synuclein leads to inclusion formation and neuronal loss of dopaminergic cells in the substantia nigra, we made transgenic mice in which the expression of wild-type or mutant (A30P and A53T) human alpha-synuclein protein was driven by the promoter from the tyrosine hydroxylase gene. Even though high levels of human alpha-synuclein accumulated in dopaminergic cell bodies, Lewy-type-positive inclusions did not develop in the nigrostriatal system. In addition, the number of nigral neurons and the levels of striatal dopamine were unchanged relative to non-transgenic littermates, in mice up to one year of age. These findings suggest that overexpression of alpha-synuclein within nigrostriatal dopaminergic neurons is not in itself sufficient to cause aggregation into Lewy body-like inclusions, nor does it trigger overt neurodegenerative changes.
Matsuoka
Y
Y
Dementia Research Group, Nathan Kline Institute/New York University Medical School, 140 Old Orangeburg Road, Orangeburg, New York 10962, USA.
Vila
M
M
Lincoln
S
S
McCormack
A
A
Picciano
M
M
LaFrancois
J
J
Yu
X
X
Dickson
D
D
Langston
W J
WJ
McGowan
E
E
Farrer
M
M
Hardy
J
J
Duff
K
K
Przedborski
S
S
Di Monte
D A
DA
D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D016631:Lewy Bodies / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009419:Nerve Tissue Proteins / Q000235:genetics*; D020734:Parkinsonian Disorders / Q000235:genetics / Q000473:pathology; D010641:Phenotype; D011401:Promoter Regions, Genetic / Q000502:physiology*; D013378:Substantia Nigra / Q000473:pathology*; D051843:Synucleins; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics*; D051844:alpha-Synuclein
D009419:Nerve Tissue Proteins; C497604:SNCA protein, human; C497605:Snca protein, mouse; D051843:Synucleins; D051844:alpha-Synuclein; D014446:Tyrosine 3-Monooxygenase