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.
Public Health Relevance Statement: Public Health Relevance: 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 certain 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. Recently, a patient with an early-onset form of PD was identified, and found to have a mutation in a certain protein, and researchers were able to prepare stem cells from a sample of the patient's skin, that can be used to form neurons in a dish. Furthermore, these neurons have proven to be sensitive to environmental toxins. We propose to develop methods so that the stem cell derived neurons from the PD patient can be used to screen chemicals that might escape into the environment for their potential to cause PD, using the stem cell-derived neurons. The methods will involve the use of automated, robotic microscopes.
NIH Spending Category: Acquired Cognitive Impairment; Aging; Brain Disorders; Dementia; Neurodegenerative; Neurosciences; Parkinson's Disease; Stem Cell Research; Stem Cell Research - Induced Pluripotent Stem Cell; Stem Cell Research - Induced Pluripotent Stem Cell - Human
Project Terms: Accounting; Affect; Age; alpha synuclein; Alzheimer's Disease; Apoptotic; arm; Back; base; Behavior; beta pleated sheet; Biological Assay; Biological Markers; Brain; Calcium; Cell Line; Cell physiology; Cells; Cessation of life; Chemicals; Cognition; Companions; Dementia; Development; Disease; dopaminergic neuron; early onset; Environment; European; Family history of; Fluo 4; Generations; genome editing; Goals; Government Agencies; Health; Herbicides; high throughput screening; Human; Incidence; induced pluripotent stem cell; Inherited; Insecticides; interest; Label; Leg; Limb structure; Link; male; men; Methods; Microscope; Midbrain structure; Mitochondria; mitochondrial dysfunction; Modeling; Moods; Motor; Mutation; National Institute of Environmental Health Sciences; National Toxicology Program; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Nitric Oxide; Nitrogen; Nitrogen Oxides; Oxygen; Parkinson Disease; Parkinson's Disease Pathway; pars compacta; Pathology; Patients; Pesticides; Pharmaceutical Preparations; Phase; Population; Prevalence; Production; programs; protein misfolding; protein structure; Proteins; Protocols documentation; Provider; public health relevance; Research; Research Personnel; response; Risk; Robotics; Sampling; Science; Skin; Small Business Innovation Research Grant; Solvents; Stem cells; Structure; Substantia nigra structure; Superoxides; Symptoms; Synapses; Testing; Toxic effect; Toxic Environmental Substances; Toxicity Tests; Toxin; Tremor; United States Environmental Protection Agency; Work; Xenobiotics
