Research Project
9020156
? DESCRIPTION (provided by applicant): Parkinson's disease (PD) is the 2nd most common neurodegenerative affliction, affecting approx. 1 % of the human population. The symptoms of PD include tremors in motor function of limbs, due to progressive death of dopaminergic neurons in the brain. While certain forms of PD are inherited, it is clear that environmental toxins, including pesticides, and, likely, industrial solvents, contribute to PD, but the pathways via which this occurs are incompletely understood. ? -Synuclein (?-Syn), a protein of unknown function, participates in PD pathology, likely due to mis-folding, aggregation, and toxicity to mitochondrial function. Further, environmental toxins, linked to PD, also inhibit mitochondrial function. A mutation in ?-Syn (A53T) has been identified which causes an early-onset of PD. Induced pluripotent stem cells (iPSCs) have been prepared from a subject harboring the ?-Syn A53T mutation, and dopaminergic neurons, derived from these iPSCs display increased PD-related responses to pesticides, compared to isogenic control iPSC cells. The goal of this Phase I SBIR project will be to develop a high throughput screen to test environmental toxins for their ability to increase the risk of PD, using iPSC-derived dopaminergic neurons harboring the A53T mutation. To identify the biomarkers that will provide the best indication of PD-related pathologies, we will test pesticides on these neurons and quantify effects on synaptic structures, mitochondria, and the generation of reactive oxygen and nitrogen species. Customers for the assay include government agencies, such as the US EPA. Vala Sciences Inc. specializes in developing cell-based assays relevant to environmental toxicity, and is an assay provider for the EPA ToxCast program. The Phase II goals will be to further refine and expand the capability of the assays that can be done with these neurons.
