Center for Research Promotion and Support, Fujita Health University, Toyoake, Aichi, Japan.
Department of Physiological Chemistry, School of Medicine, Fujita Health University, Toyoake, Aichi, Japan.
J Neural Transm (Vienna). 2023 May;130(5):611-625. doi: 10.1007/s00702-023-02617-6. Epub 2023 Mar 20.
The dark pigment neuromelanin (NM) is abundant in cell bodies of dopamine (DA) neurons in the substantia nigra (SN) and norepinephrine (NE) neurons in the locus coeruleus (LC) in the human brain. During the progression of Parkinson's disease (PD), together with the degeneration of the respective catecholamine (CA) neurons, the NM levels in the SN and LC markedly decrease. However, questions remain among others on how NM is associated with PD and how it is synthesized. The biosynthesis pathway of NM in the human brain has been controversial because the presence of tyrosinase in CA neurons in the SN and LC has been elusive. We propose the following NM synthesis pathway in these CA neurons: (1) Tyrosine is converted by tyrosine hydroxylase (TH) to L-3,4-dihydroxyphenylalanine (L-DOPA), which is converted by aromatic L-amino acid decarboxylase to DA, which in LC neurons is converted by dopamine β-hydroxylase to NE; (2) DA or NE is autoxidized to dopamine quinone (DAQ) or norepinephrine quinone (NEQ); and (3) DAQ or NEQ is converted to eumelanic NM (euNM) and pheomelanic NM (pheoNM) in the absence and presence of cysteine, respectively. This process involves proteins as cysteine source and iron. We also discuss whether the NM amounts per neuromelanin-positive (NM) CA neuron are higher in PD brain, whether NM quantitatively correlates with neurodegeneration, and whether an active lifestyle may reduce NM formation.
黑色素（NM）在人类大脑的黑质（SN）中的多巴胺（DA）神经元和蓝斑核（LC）中的去甲肾上腺素（NE）神经元的细胞体中含量丰富。在帕金森病（PD）的进展过程中，伴随着相应的儿茶酚胺（CA）神经元的退化，SN 和 LC 中的 NM 水平显著降低。然而，人们仍然存在一些疑问，例如 NM 如何与 PD 相关，以及它是如何合成的。由于在 SN 和 LC 的 CA 神经元中存在酪氨酸酶的存在一直难以捉摸，因此 NM 在人类大脑中的生物合成途径一直存在争议。我们提出了这些 CA 神经元中 NM 合成途径：（1）酪氨酸通过酪氨酸羟化酶（TH）转化为 L-3,4-二羟基苯丙氨酸（L-DOPA），L-DOPA 被芳香族 L-氨基酸脱羧酶转化为 DA，DA 在 LC 神经元中被多巴胺β-羟化酶转化为 NE；（2）DA 或 NE 自动氧化为多巴胺醌（DAQ）或去甲肾上腺素醌（NEQ）；（3）DAQ 或 NEQ 在不存在和存在半胱氨酸的情况下分别转化为真黑色素（euNM）和褐黑色素（pheoNM）。这个过程涉及到作为半胱氨酸来源的蛋白质和铁。我们还讨论了 PD 大脑中每个 NM 阳性（NM）CA 神经元中的 NM 含量是否更高，NM 是否与神经退行性变定量相关，以及积极的生活方式是否可能减少 NM 的形成。
