Biosynthetic pathway to neuromelanin and its structural modification in aging : Incorporation of neurotoxic molecules in neuromelanin

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The biosynthesis and structure of neuromelanin(NM) still remains poorly understood. Using model compounds of the melanic component of NM prepared by tyrosinase oxidation at various ratios of dopamine(DA) and cysteine(Cys) under physiological conditions, we performed a biosynthetic and biodegradative(aging) study by following the time course of oxidation to NM and the subsequent biodegradation of NM under various heating conditions. By following the time course of the biosynthetic pathway of synthetic NM we found that the neurotoxic molecules are trapped in NM. By comparing the ratios of the degradation markers, natural NM was found to be similar to aged(heated) NM prepared from a 2 : 1 molar ratio of DA and Cys, which can be used as a model of natural NM. A method to prepare synthetic NM that mimics the melanic component of human NM structurally was now established, i. e., tyrosinase oxidation of DA+Cys in a ratio of 2 : 1 followed by heating at 37℃for 40 days. This preparation of model NM should facilitate studies elucidating the physiological roles of NM during the aging process and its roles in the etiology pathogenesis of PD.