Neuroprotection against Aminochrome Neurotoxicity: Glutathione Transferase M2-2 and DT-Diaphorase

Abstract

Glutathione is an important antioxidant that plays a crucial role in the cellular protection against oxidative stress and detoxification of electrophilic mutagens, and carcinogens. Glutathione transferases are enzymes catalyzing glutathione-dependent reactions that lead to inactivation and conjugation of toxic compounds, processes followed by subsequent excretion of the detoxified products. Degeneration and loss of neuromelanin-containing dopaminergic neurons in the nigrostriatal neurons generally involves oxidative stress, neuroinflammation, alpha-synuclein aggregation to neurotoxic oligomers, mitochondrial dysfunction, protein degradation dysfunction, and endoplasmic reticulum stress. However, it is still unclear what triggers these neurodegenerative processes. It has been reported that aminochrome may elicit all of these mechanisms and, interestingly, aminochrome is formed inside neuromelanin-containing dopaminergic neurons during neuromelanin synthesis. Aminochrome is a neurotoxic ortho-quinone formed in neuromelanin synthesis. However, it seems paradoxical that the neurotoxin aminochrome is generated during neuromelanin synthesis, even though healthy seniors have these neurons intact when they die. The explanation of this paradox is the existence of protective tools against aminochrome neurotoxicity composed of the enzymes DT-diaphorase, expressed in these neurons, and glutathione transferase M2-2, expressed in astrocytes. Recently, it has been reported that dopaminergic neurons can be protected by glutathione transferase M2-2 from astrocytes, which secrete exosomes containing the protective enzyme.

In vivoreduction of age-dependent neuromelanin accumulation mitigates features of Parkinson’s disease

“… 57 In this context, it is important to recall that DAT is also expressed in astrocytes and macrophages, which contribute to DA clearance from the synaptic cleft. 48 , 49 The increased number of CD68- and GFAP-positive cells in AAV-TYR-injected animals could thus favor an increased DA uptake and metabolism in glial cells, which is consistent with increased 3MT levels observed in the ventral midbrain of AAV-TYR-injected animals at 2 months post-AAV injection ( Supplementary Table 6 ) and that could restrict the amount of DA available to be re-uptaken by neuronal DAT. All these changes in DA metabolism, combined with the progressive buildup of NM within the neuronal cytosol, may potentially contribute to the vulnerability of the dopaminergic system in TYR animals and in PD patients.…”

Neuroprotective Capability of Narcissoside in 6-OHDA-Exposed Parkinson’s Disease Models through Enhancing the MiR200a/Nrf-2/GSH Axis and Mediating MAPK/Akt Associated Signaling Pathway

“…Some reports have shown that the disruption of iron homeostasis due to iron accumulation in dopamine neurons has been implicated in Parkinson’s disease [ 55 ]. GST catalyzes the modifying reaction of the reduced form of GSH to xenobiotic substrates in order to promote the solubility of xenobiotic substrates and prevent them from interacting with intracellular proteins and nucleic acids, to achieve the purpose of detoxification [ 56 ]. Therefore, the activation of Nrf2, in addition to increasing the amount of downstream GSH, should initiate multiple neuroprotective and antioxidative mechanisms, although these were not analyzed in this study.…”

In vivo reduction of age-dependent neuromelanin accumulation mitigates features of Parkinson’s disease

“…Furthermore, we have previously reported that striatal DAT levels are decreased by ∼70% in AAV-TYR-injected animals by 2 months post-AAV-TYR injections 5 , which concur with neuroimaging in vivo analyses in PD patients exhibiting reductions in DAT striatal density at early stages of the disease 51 . In this context, it is important to recall that DAT is also expressed in astrocytes and macrophages, which contribute to DA clearance from the synaptic cleft 46,47 . The increased number of CD68- and GFAP-positive cells in AAV-TYR-injected animals could thus favor an increased DA uptake and metabolism in glial cells, which is consistent with increased 3MT levels observed in the ventral midbrain of AAV-TYR-injected animals at 2 months post-AAV injection (Supplementary Table 4) and that could restrict the amount of DA available to be re-uptaken by neuronal DAT.…”

“…The regulation of the balance of cytosolic DA levels is complex and involves an interplay between different processes. From one hand, dopamine transporter (DAT)-mediated reuptake of extracellular DA [45][46][47] , leaking from synaptic vesicles, and TH-mediated DA synthesis increase cytosolic DA levels. On the other hand, VMAT2-mediated DA encapsulation into synaptic vesicles and MAO-mediated DA metabolism decrease cytosolic DA levels 48 .…”