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

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.

Keywords: Dopamine; Locus coeruleus; Melanin; Neuromelanin; Norepinephrine; Parkinson’s disease; Substantia nigra; Tyrosinase; Tyrosine hydroxylase.

Fig. 1

Historic overview of findings and hypotheses in the elucidation of the biosynthesis pathway of neuromelanin (NM). In 1950, Fitzpatrick et al. (1) demonstrated the presence of tyrosinase in melanocytes of peripheral tissues, which (2) fueled the understanding of the role of this enzyme in the biosynthesis of melanin in melanocytes with DOPAquinone as intermediate. (3) Originally, it was speculated that NM was synthesized from tyrosine by a similar pathway as peripheral melanin. (4) However, tyrosinase had not been found in CA neurons, so it was unclear how tyrosine could enter the NM synthesis pathway, and even to date the presence of tyrosinase in DA or NE neurons in the SN and LC of human brain remains elusive. (5) Then, in 1964, Nagatsu et al. identified the enzyme tyrosine hydroxylase form bovine adrenal medulla as an enzyme that catalyzes the conversion of tyrosine to L-DOPA. This finding contributed to (6) the gradual elucidation of the NM biosynthesis pathway which continues to this day. In 1987, the human genes for both tyrosinase (7) (Kwon et al. 1987) and tyrosinase hydroxylase (8) (Grima et al. ; Kaneda et al. ; Kobayashi et al. 1987) were identified. (9) More details of the chemistry of melanin and NM keep gradually being revealed until this day. (10) Autoxidation of DA or NE is commonly believed to be the (major) route of how these two molecules can enter the NM synthesis pathway, but some authors believe that (also) enzymatic routes are of importance (e.g., Carballo-Carbajal et al. 2019)

Fig. 2

Biosynthesis pathways of eumelanin (EM) and pheomelanin (PM) in melanocytes in peripheral tissues (i.e., skin and hair) and of eumelanic portion of NM (euNM) and pheomelanic portion of NM (pheNM) in human brain. The eumelanic pigments are usually darker and brown or black in color, while the pheomelanic pigments are lighter and more yellowish/reddish in color. Eumelanin and pheomelanin differ not only in color but also in their redox, metal chelating, and free radical scavenging properties. Eumelanin is an antioxidant, more stable, and photoprotective, while pheomelanin is more prone to photodegradation and can act as a pro-oxidant by either reducing antioxidants or generating reactive oxygen species (d'Ischia et al. 2013). For brain NM, the scheme represents the initial steps of the growing melanic portion of NM, a very complex pathway that later involves more proteins, lipid and metals at various steps and the biogenesis of NM-organelles. DAQ: DAquinone; NEQ: NEquinone; DAC: DAchrome; DHI: 5,6-dihydroxyindole; 5SCDA: 5-S-cysteinyldopamine; 5SCNE: 5-S-cysteinylnorepinephrine; DQ: DOPAquinone; DC: DOPAchrome; DHICA: 5,6-dihydroxyindole-2-carboxylic acid; 5SCD: 5-S-cysteinyldopa; Tyr: tyrosine; Tyrp1: tyrosine-related protein 1; Tyrp2: tyrosine-related protein 2. Enzyme names are shown in italic for the sake of clarity. (O): oxidant (Reference: Nagatsu et al.2022). Although in mice Tyrp1 acts as a DHICA oxidase as indicated in the figure, its human homolog may not act in the same way and its precise enzymatic function is not yet clear (Boissy et al. 1998)

Fig. 3

Simplified graph figures of how, theoretically, the distribution of cellular NM concentrations among NM⁺ CA neurons in the SN or LC may compare between PD patients (dashed gray line) and controls (black line) if A there is no difference in PD neurodegeneration related to NM concentrations per cell, B if in PD the NM concentrations per cell are not higher than in controls and if in PD those cells with a higher NM content are more likely to die, and C if in PD the NM concentrations per cell are higher than in controls and if in PD those cells with a higher NM concentration are more likely to die. It is not precisely known how NM concentrations are distributed per CA neurons, and the shapes of the graphs in this figure are partly speculative; the figure is only meant as a visual aid in a theoretical discussion