(PLEASE KEEP IN WORD, DO NOT PDF) The erythroid iron restriction response suppresses erythropoiesis during iron deprivation and leads to iron deficiency anemia (IDA), one of the most common nutritional disorders in the world. This response differs among individuals such that a similar degree of iron deficiency can lead to variable degrees of anemia within a population. The heterogeneity of this response has implications for patient management in several settings: phlebotomy for polycythemia vera, intravenous (IV) iron for anemia of renal failure, donation frequency for red cell donors. Factors that contribute to this variability are unknown. Delineating pathways that modulate the erythroid iron restriction response between individuals will enable superior calibration of iron-targeting therapies and guide novel therapeutic strategies. a-Synuclein, outside its neural role, has been known as an erythroid factor; in mature human RBC it represents the 13th most abundant protein. It interacts with iron and regulates iron trafficking proteins. Red cell a-synuclein in normal human donors assumes multiple physical forms and varies markedly in its levels among individuals (>2-fold). A direct modifier of a-synuclein self-assembly consists of dopamine, and loading of dopamine occurs in red cells. Strikingly, no clear function for -synuclein or dopamine has been established in erythropoiesis. We addressed whether -synuclein affects the erythroid iron deprivation response by comparing Snca+/- and +/+ littermates on control vs low iron diets. These experiments model the ~2-fold variation seen in human populations. No hematologic differences existed between +/- and +/+ mice on control diet. However, strong differences occurred with the low iron diet: Snca+/- mice had a blunted iron restriction response reflected in the red cell counts/indices, platelet levels, and serum erythropoietin levels. No differences were seen in serum hepcidin levels at baseline or with iron perturbations. Mining a red cell metabolomic dataset from human blood donors -/+ iron deficiency revealed dopamine as the top metabolite downregulated in red cells in association with iron deficiency anemia. We then found that low-dose dopamine treatment of ex vivo cultured human erythroid progenitors reversed the growth-inhibitory effects of iron deprivation. Our findings thus show: 1) an in vivo influence of -synuclein dosage only in the setting of iron deficiency, 2) an in vivo decrease in erythroid dopamine associated with iron deficiency, and 3) a pro-erythroid influence of dopamine in ex vivo erythroid cultures. We therefore propose a pathway in which iron regulates erythropoiesis via dopamine modulation of -synuclein status. This project will elucidate unexplored features of the iron restriction response, features with potential to guide future treatment approaches.