Parkinson's Disease (PD) is the second most common neurodegenerative disorder with resting tremor, muscle rigidity, bradykinesia and postural instability as primary diagnostic signs. The movement dysfunction results from specific degeneration of dopaminergic neurons in the substantia nigra. The neuropathological hallmark of PD is the Lewy body, a cytoplasmic inclusion largely composed of fibrils formed by the polymerized, presynaptic protein alpha-synuclein. The point mutations A53T and A30P in the alpha-synuclein gene are linked to an autosomal dominant form of familial PD suggesting that a toxic gain of function may participate in the pathophysiology of PD. As C. elegans has shown to be a powerful model organism for the study of human neurological diseases like Alzheimer's Disease and Huntington's Disease, we established a nematode model for PD based on the expression of human alpha-synuclein. We generated worms carrying extrachromosomal and integrated arrays of human wildtype and mutant alpha-synuclein controlled by the C. elegans promoters
unc-119 and
sel-12 . Transgenic worms containing constructs expressing alpha-synuclein in neurons produce axonal deposits with strong anti alpha-synuclein immunoreactivity implying transport to the presynapse and aggregation in the axon. Furthermore, we detected a high molecular alpha-synuclein aggregate that migrated in the stacking gel in immunoblotted worm protein extracts. Transgenic C. elegans expressing human alpha-synuclein display noticeable phenotypes including locomotor dysfunction, egg laying defect and morphological abnormalities suggesting alpha-synuclein toxicity. As it has been reported for the Drosophila model of PD we did not detect major phenotypic differences between worms containing wild type or mutant alpha-synuclein. Experiments to determine the fate of the dopaminergic neurons and the structure of alpha-synuclein deposits in the transgenic animals are in progress. In summary, we have created a transgenic model of PD that replicates key features of PD pathology.