Toxicodietary and genetic determinants of susceptibility to neurodegeneration

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DESCRIPTION (provided by applicant): We propose a USA/DRC collaborative project to elucidate the relationship between food (cassava, Manihot esculenta Crantz) cyanogenic toxins and the occurrence of a motor system disease --- known as konzo --- in sub-Saharan Africa. The causes of konzo have largely remained unclear, and other forms of cassava-related neurodevelopmental/cognitive impairment may exist during childhood and adult life. We will bring together country-specific research capabilities and needs to reach the following goals: (a) illuminate the impact of cassava neurotoxicity on human motor and cognition abilities, (b) increase understanding of lifespan interactions between environmental stressors (toxicants), diet (nutritional status), and genetics in relation to motor system degeneration, (c) and enhance the clinical/neurotoxicolgy research capacity of the Democratic Republic of Congo (DRC). Our central hypothesis is that risk for cassava-associated motor/cognition deficits (MCD) is determined by chronic sulfur amino acid-deficiency and/or genetic variations that impair the metabolism of cassava cyanogens with subsequent increase in cyanate (neurotoxin) production and risk for neurodegeneration. To test our hypothesis and achieve our goals, we will address the following specific aims: (1) elucidate the epidemiological pattern of motor cognition deficits (MCD) associated with chronic dietary reliance on cassava, (2) determine the risk for MCD in relation to sulfur amino acid deficiency and genetic polymorphisms in the cyanogen-detoxifying enzyme rhodanese (thiosulfate sulfurtransferase), and (3) increase the manpower for clinical/neurotoxicology research in DRC. MCD will be ascertained by neuropsychological testing in a cross-sectional study (baseline characterization) followed by a case-cohort design to capture neurodevelopmental delays in school-age children. TST polymorphisms will be studied using PCR-based sequencing techniques. Serum carbamoylation will be analyzed and quantified using state-of-the-art proteomic methodologies i.e. liquid chromatography tandem mass spectrometry (LC/MS-MS). Young DRC investigators will be trained through active participation in supervised field work and mentoring for career development. Relevance. At the completion of the proposed studies, our findings will help develop a scientific rationale to address and develop strategies to reduce the burden of neurotoxicity associated with cassava, a staple food for more than 500 million people around the globe. The overall goal of this proposal meshes well with the global health mission of the NIH while integrating the institute-specific missions of FIC, NIEHS, NINDS, and NICHD. PUBLIC HEALTH RELEVANCE: We propose research activities of global health significance to elucidate risk factors for konzo (irreversible paralysis) or cognition deficits that occur among populations that rely on cyanogenic cassava (aka manioc, or tapioca, or yucca) as staple food. Because konzo mostly affects children and women, and cassava is a staple for more than 500 million people around the globe, understanding its neurotoxicity potential is pertinent to global health, economy, and security. Our results will also help regulating agencies set safety standards in relation to international trade and consumption of other cyanogenic foods (e.g. lima beans) or cyanogenic exposure in occupational settings (e.g. painting industries, or gold mining, or theatres of wars).