Genetic background, pesticide exposure, age, gender, diet and lifestyle are implicated risk factors in Parkinson's disease. We demonstrate dopamine neuron loss and other features of Parkinsonism based on the interaction of several of these human risk factors in transgenic mice expressing human alpha-synuclein. Mice expressing different forms of human alpha-synuclein had progressive declines in locomotor activity and abnormal responses to apomorphine that were modified by transgenic status. Stereological counts of tyrosine hydroxylase-positive neurons significantly declined with age only in the transgenic lines, consistent with a constant or decreasing risk, with the line expressing a double-mutant form of human alpha-synuclein more severely affected than the line expressing wild-type human alpha-synuclein. Treatment with Mn2+-ethylenebisdithiocarbamate and paraquat resulted in significantly greater effects in the double-mutant line than the other lines. Inclusions were not identified in the transgenic lines. Overexpression of human alpha-synuclein had adverse effects on substantia nigra pars compacta dopaminergic neurons that were modified by risk factors interacting in humans, including human alpha-synuclein mutations, ageing, and exposure to pesticides.