While the majority of ParkinsonŐs disease (PD) cases are sporadic, with no known cause, there are rare familial forms of the disease. The first gene identified as causing ParkinsonŐs disease is a-synuclein (SNCA). To date, 3 missense SNCA mutations have been identified as causing early onset autosomal dominant ParkinsonŐs disease. Triplication of the normal SNCA gene also causes early onset PD, while a duplication causes a late onset familial form of the disease. In sporadic cases of PD, intracellular inclusions called Lewy bodies are commonly seen in remaining nigral dopaminergic neurons. SNCA is a major component of these inclusions. To study how SNCA causes PD, we are utilizing transgenic mice that express A53T mutant and WT forms of the human protein. A53T mutant SNCA causes a fatal motor neuron axonopathy when over expressed in spinal cord. While spinal cord motor neurons are not affected in PD, our hypothesis is that the mechanism of SNCA toxicity is the same in motor neurons and those neurons affected in PD. The accessibility of motor neurons axons compared to those of the central nervous system makes these mice useful for studying how SNCA triggers axonal degeneration. Currently, we are using microarray analysis to examine transcriptional changes triggered by the presence of mutant SNCA. Analysis of the spinal cord pathology, which includes the occurrence of SNCA-positive inclusions, and examination of axonal function and the state of SNCA in diseased axons are other areas of interest.