Catecholamines-up modulates alpha-synuclein- induced neurotoxicity in a Parkinsons disease model. Rami R Ajjuri, Faiza Ferdousy, Janis M. O'Donnell. Department of Biology, University of Alabama, Box 870344, Tuscaloosa, AL, 35487-0344.

   While alpha-synuclein has been widely studied in respect to Parkinsons disease (PD) pathology, the exact mechanisms underlying its role in neurotoxicity have not yet been elucidated. As dopamine neurons in the substantia nigra are preferentially damaged during early stages of PD, much research has been devoted to the role of alpha-synuclein in relation to the production and homeostasis of dopamine, a vital neurotransmitter. Catsup, or Catecholamines-up, plays a critical role in negatively regulating GTP cyclohydrolase and tyrosine hydrolase, key components of the dopamine biosynthesis pathway, and has been shown to modify neurotoxicity in a paraquat-induced PD model in Drosophila. We report that expression of wildtype human alpha-synuclein and human alpha-synuclein mutant (A30P) result in the reduction of tyrosine hydroxylase activity as well as a reduction of dopamine levels. We also observe an increase in dopamine turnover, indicating dysfunction of vesicular packaging. When expressed in the Catsup loss-of-function mutant background, however, both dopamine levels and turnover in wild type alpha-synuclein and A30P mutant transgenic flies are rescued. Similarly, dopamine neurons in Catsup mutants expressing wild type or the A30P mutant forms of alpha-synuclein were significantly protected when compared with those expressing alpha-synuclein wt or the A30P mutant form alone. These results indicate a potentially important role for Catsup in modulating the detrimental effects of alpha-synuclein expression in Parkinsons disease pathology.