1. Modeling Parkinson's disease in mice:

Several approaches have been taken to model PD in animals, including transgenic mice, viral transduction of Snca, and chemical models in which nigral dopaminergic neurons are preferentially targeted.  To date, none of these approaches has fully recapitulated PD.Dopaminergic neurons are not the only affected cell types in PD; rather the disease begins in the brainstem, also affects the enteric nervous system, and slowly progresses through the mid-brain, eventually affecting regions of the cerebral cortex.  Transgenic approaches using heterologous promoters have generated animals that develop synucleinopathies, but generally in tissues not affected in PD.  Viral transduction techniques target the substantia nigra, and thus other regions of the nervous system affected in PD are spared.  This system also requires stereotactic injection of every animal.  Chemical methods that kill dopaminergic neurons produce animals that may be useful for examining drugs to ameliorate symptoms caused by loss of those neurons, but again do not target all regions affected in PD, and the mechanisms by which various toxins kill dopaminergic neurons may be irrelevant to sporadic PD.  Thus these models are not be useful in examining the early stages of the disease which cannot be studied in humans.

 

Our approach is to generate transgenic mice that express SNCA under the regulation of its own promoter.   One WT SNCA transgenic line of this type has been generated, and the pattern of SNCA expression examined.  No aberrant expression has been found, thus demonstrating that the genomic PAC cloned used contains all the promoter information needed to drive appropriate expression of the transgene.  These WT SNCA transgenic mice do not highly overexpress SNCA, however, and live a normal lifespan.  Subtle changes in the nigra and striatum at advanced ages may indicate the beginning of SNCA-driven pathology.  To induce disease at an earlier age, the PAC has been mutated to introduce the A53T mutation that causes PD in humans, and transgenic lines carrying the mutant PAC are now being analysed for appropriate expression patterns.  Such lines will be aged and assessed for development of PD-like pathology.