Sensitivity to MPTP is not increased in Parkinson's disease-associated mutant alpha-synuclein transgenic mice

Environmental and genetic factors that contribute to the pathogenesis of Pa rkinson's disease are discussed. Mutations in the alpha -synuclein (alpha S YN) gene are associated with rare cases of autosomal-dominant Parkinson's d isease. We have analysed the dopaminergic system in transgenic mouse lines that expressed mutant [A30P]alpha SYN under the control of a neurone-specif ic Thy-1 or a tyrosine hydroxylase (TH) promoter. The latter mice showed so mal and neuritic accumulation of transgenic [A30P]alpha SYN in TH-positive neurones in the substantia nigra. However, there was no difference in the n umber of TH-positive neurones in the substantia nigra and the concentration s of catecholamines in the striatum between these transgenic mice and non-t ransgenic littermates. To investigate whether forced expression of [A30P]al pha SYN increased the sensitivity to putative environmental factors we subj ected transgenic mice to a chronic 1-methyl-4-phenyl-1,2,3.6-tetrahydropyri dine (MPTP) regimen. The MPTP-induced decrease in the number of TH-positive neurones in the substantia nigra and the concentrations of catecholamines in the striatum did not differ in any of the [A30P]alpha SYN transgenic mou se lines compared with wild-type controls. These results suggest that mutat ions and forced expression of alpha SYN are not likely to increase the susc eptibility to environmental toxins in vivo.