Ninety-nine percent of alpha-synuclein (α-syn) in the human body is distributed in erythrocytes. However, the role that α-syn plays in erythropoiesis remains unclear. To determine the effect of α-syn on erythroid differentiation, the erythroid cells, derived from human CD34+ progenitors in the umbilical cord, were cultured in a system composed of a series of cytokines and harvested after 6 days. Our work showed α-syn inhibition-promoted erythropoiesis as characterized by altered activity of surface markers of erythroid development such as CD49d, CD36, and CD71; and different methylation status of GDP-D-mannose dehydratase, aldolase fructose-bisphosphate A, and sorbitol dehydrogenase, key enzymes involved in fructose and mannose metabolism. Reduced adenosine triphosphate and elevated lactic acid also suggested a shift in cellular metabolism from mitochondrial respiration to glycolysis. Our study revealed a previously unknown role for α-syn as a methylation regulator that alters the activity of key enzymes of the fructose and mannose metabolism, thus contributing to erythropoiesis.
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