Neuromelanin in Parkinson’s Disease: Tyrosine Hydroxylase And Tyrosinase Part 3
Apr 15, 2024
Alternatively, NM in DA neurons has generally been regarded as acting for neuroprotection, since NM inactivates toxic free radical species via its ability to chelate transition metals, especially iron. Iron also accumulates in DA neurons [112,115–117].
DA neurons are a type of neuron in the brain that are often closely related to behaviors such as reward, attention, and motivation. However, as research continues to deepen, scientists have discovered that DA neurons may also be closely related to memory.
Researchers once found in mouse experiments that activating DA neurons can enhance the performance of mice in spatial and object recognition tasks, which illustrates the positive impact of DA neurons on memory ability. In addition, in humans, DA neurons have also been found to be related to the formation and maintenance of memory, and also play an important role in learning and cognitive functions.
Specifically, DA neurons share a neural circuit called the "hippocampal-ventral 'VTA' area" (HP/VTA), which is thought to have profound effects on memory and emotional behavior. When a person is learning new things, DA neurons are activated and release chemicals such as dopamine to enhance the learning effect and enhance the brain's memory of the stimulus. This is why when you are learning, you will feel excited and happy, and it is also easy to remember what you have learned.
In addition, research shows that DA neurons can also help us better store information by controlling eye gaze, which is also known as "visually induced modulated memory." Researchers have found that when our eyes scan over objects we want to remember, DA neurons are activated and help us better store this information.
In short, although the role of DA neurons in the brain is very complex, its impact on memory is very positive and positive. Therefore, we should take good care of our neurons and improve our memory and cognitive functions through learning, exercise, and a healthy lifestyle. It can be seen that we need to improve memory, and Cistanche deserticola can significantly improve memory, because Cistanche deserticola can also regulate the balance of neurotransmitters, such as increasing the levels of acetylcholine and growth factors. These substances are very important for memory and learning. In addition, Cistanche deserticola can also improve blood flow and promote oxygen delivery, which can ensure that the brain receives sufficient nutrients and energy, thereby improving brain vitality and endurance.
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Iron is bound to NM in the ferrous (II) iron form, a redox-active form that is involved in a Fenton-like reaction to produce toxic free radical species. NM also eliminates various toxic substances in the cytoplasm.
Thus, NM may act for neuroprotection also in vivo. However, during the progress of PD, the release of toxic substances bound to NM owing to intracellular NM degradation may result in the activation of microglia to release cytotoxic cytokines that produce neuroinflammation and neurodegeneration [78,118]. PD occurs spontaneously only in humans.
To produce the PD phenotype in various models of PD in mammals such as in mice and rats that nearly lack NM in the brain, it is necessary to trigger the DA neurodegeneration by some toxic chemicals such as 1-phenyl-4-methyl-1,2,3,6-tetrahydropyridine (MPTP) that inhibits the mitochondrial complex I [97].
Vila's group reported that NM accumulation in DA neurons during aging over a threshold causes DA neuron death and PD phenotype [119–121]. They created a rat model of human PD by overexpression of human NM in the right SNpc by stereotaxic injection of an adeno-associated viral (AAV) vector expressing human tyrosinase [119].
The rats showed age-dependent production of human-like NM within nigral DA neurons, up to levels in elderly humans. Intracellular NM aggregation above a specific threshold is associated with an age-dependent PD phenotype, including hypokinesia.
Enhancing lysosomal proteostasis reduces intracellular NM and prevents neurodegeneration in tyrosinase-overexpressing rats. Intracellular NM levels may set the threshold for the initiation of PD. Furthermore, extracellular NM leaked from dead NM-containing DA neurons may activate microglia to produce neuroinflammation and further promote DA cell death [122].
NM is a hot candidate to trigger PD and/or to lead to progressed degeneration of PD, however, there are unsolved problems arising from the treatment of PD with levodopa: (1) Post-mortem data have not shown an increase of NM in surviving NM containing dopaminergic neurons of the SN after levodopa long term treatment and (2) long term levodopa treatment has not demonstrated a significant increase in the progression of PD.
The NM theory is a fit for the phenotypes of human sPD. In addition, there is much evidence on the cytotoxicity of α-synuclein [10,19,123].
Recently, the role of NM in inducing α-synuclein expression and aggregation has been suggested as a mechanism for this pigment to modulate neuronal vulnerability in PD [124]. α-Synuclein reacts with tyrosinase, and the chemical modifications on the tyrosinase-treated α-synuclein strongly influence its aggregation properties and increase toxicity, and α-synuclein may influence the synthesis of NM [125,126].
Iron redox chemistry promotes the aggregation of α-synuclein, and protein-metal complex aggregates are directly involved in ROS production, exacerbating the oxidative damage [127]. Furthermore, DA neurons easily express MHC-I, and induction of MHC-I is promoted by activation of microglia either by α-synuclein or by NM, as well as by interferon-gamma or high cytosolic DA and oxidative stress [128].
The activated microglia in PD brains express major histocompatibility complex class II (MHC-II) molecules. The number of MHC-II positive microglia in the SN and putamen increases as the neuronal degeneration of the SN proceeds [129].
An evolution theory has been proposed to explain human-specific PD based on the greater development of the human cerebral cortex than that of basal ganglia [130–132]. Clinically, PD is a systemic disease, and it is difficult to explain the degenerative processes, especially in the autonomic nervous system, exclusively by NM theory, although there is accumulating evidence that the pathogenesis of PD is complex and involves energy metabolism disorders, oxidative stress, proteasomal abnormalities, α-synuclein accumulation, alterations of gut microbiota metabolites, and neuroinflammation [133,134]. In this context, the evolutional point of view on the NM system and α-synuclein system is also of interest.
4. Conclusions
Neuromelanin (NM) is thought to be synthesized by the following pathway: tyrosine →(TH)→ DOPA → (AADC)→ DA → (non-enzymatic oxidation or tyrosinase) → DAQ --→ euNM/pheoNM.
Finding neuromelanin-specific tyrosinase (activity) and DAC tautomerase (activity) remains for future study as an important problem in the pathophysiology of PD. NM is considered to act both for neuroprotection and for cell death of DA neurons depending on the intracellular levels of accumulation.
The pathophysiology of NM about α-synuclein is another important project for elucidating the cause of PD.
Author Contributions: Conceptualization, all authors; writing-original draft preparation, T.N.; writing-review and editing, K.W., S.I., H.W. and A.N.; visualization, K.W., and A.N. All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict of interest.
Abbreviations
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