Strengths and limitations of genetic mouse models of Parkinson's disease

Genetic mouse models based on alpha-synuclein overexpression are particularly compelling because abnormal accumulation of alpha-synuclein occurs in sporadic Parkinson's disease (PD). Our laboratory has characterized a mouse overexpressing wild-type human alpha-synuclein under the Thy1 promoter, which confers broad expression of the transgene in neurons. These mice show progressive sensorimotor anomalies starting at 2 months of age, as well as olfactory and digestive deficits similar to those observed in patients at early stages of PD. Patterns of gene expression examined in nigrostriatal neurons isolated by single-cell laser capture microdissection in these mice at 6 months of age show an upregulation of defence mechanisms including increased levels of genes involved in proteasome and mitochondrial function, as well as cholesterol biosynthesis. At the same time, numerous alterations in genes encoding ion channels suggest that changes in the cellular function of these neurons occur independently of cell death. These data provide information on the early effects--in a mammalian brain--of a mutation known to cause PD, and they identify a number of useful end points for evaluating potential neuroprotective therapies that could interfere with the pathophysiological mechanisms of PD upstream of neuronal cell death.