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

Research output: Contribution to journalReview articlepeer-review

18 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)611-625
Number of pages15
JournalJournal of Neural Transmission
Volume130
Issue number5
DOIs
Publication statusPublished - 05-2023

All Science Journal Classification (ASJC) codes

  • Neurology
  • Clinical Neurology
  • Psychiatry and Mental health
  • Biological Psychiatry

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