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The aggregation of α-synuclein is a hallmark of Parkinson's disease (PD) and a variety of related neurological disorders. A number of mutations in this protein, including A30P and A53T, are associated with familial forms of the disease. Patients carrying the A30P mutation typically exhibit a similar age of onset and symptoms as sporadic PD, while those carrying the A53T mutation generally have an earlier age of onset and an accelerated progression. We report two  C. elegans  models of PD (PD A30P  and PD A53T ), which express these mutational variants in the muscle cells, and probed their behavior relative to animals expressing the wild-type protein (PD WT ). PD A30P  worms showed a reduced speed of movement and an increased paralysis rate, control worms, but no change in the frequency of body bends. By contrast, in PD A53T  worms both speed and frequency of body bends were significantly decreased, and paralysis rate was increased. α-Synuclein was also observed to be less well localized into aggregates in PD A30P  worms compared to PD A53T  and PD WT  worms, and amyloid-like features were evident later in the life of the animals, despite comparable levels of expression of α-synuclein. Furthermore, squalamine, a natural product currently in clinical trials for treating symptomatic aspects of PD, was found to reduce significantly the aggregation of α-synuclein and its associated toxicity in PD A53T  and PD WT  worms, but had less marked effects in PD A30P . In addition, using an antibody that targets the N-terminal region of α-synuclein, we observed a suppression of toxicity in PD A30P , PD A53T  and PD WT  worms. These results illustrate the use of these two  C. elegans  models in fundamental and applied PD research.

Comparative Studies in the A30P and A53T α-Synuclein C. elegans Strains to Investigate the Molecular Origins of Parkinson's Disease