The role of tyrosine hydroxylase as a key player in neuromelanin synthesis and the association of neuromelanin with Parkinson’s disease

Toshiharu Nagatsu, Akira Nakashima, Hirohisa Watanabe, Shosuke Ito, Kazumasa Wakamatsu, Fabio A. Zucca, Luigi Zecca, Moussa Youdim, Maximilian Wulf, Peter Riederer, Johannes M. Dijkstra

研究成果: ジャーナルへの寄稿総説査読

18 被引用数 (Scopus)

抄録

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.

本文言語英語
ページ(範囲)611-625
ページ数15
ジャーナルJournal of Neural Transmission
130
5
DOI
出版ステータス出版済み - 05-2023

All Science Journal Classification (ASJC) codes

  • 神経学
  • 臨床神経学
  • 精神医学および精神衛生
  • 生物学的精神医学

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