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 incl usions, which are one of the pathologic hallmarks of idiopathic Parkinson's disease. Mutations in alpha -synuclein have been found to be responsible f or rare familial cases of Parkinsonism. To test whether overexpression of h uman a-synuclein leads to inclusion formation and neuronal loss of dopamine rgic cells in the substantia nigra, we made transgenic mice in which the ex pression of wild-type or mutant (A30P and A53T) human alpha -synuclein prot ein was driven by the promoter from the tyrosine hydroxylase gene. Even tho ugh 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 striata l dopamine were unchanged relative to non-transgenic littermates, in mice u p to one year of age. These findings suggest that overexpression of alpha - synuclein within nigrostriatal dopaminergic neurons is not in itself suffic ient to cause aggregation into Lewy body-like inclusions, nor does it trigg er overt neurodegenerative changes. (C) 2001 Academic Press.