HYPOTHESIS
Aminochrome, the endogenous neurotoxin that triggers Parkinson's disease
Although 67 years have passed since the discovery that the motor symptoms of idiopathicParkinson’s disease are related to the massive loss of neuromelanin-containing neurons in the nigrostriatal system, it is still unclear what triggers the degenerative process of this neuronal system.
Although the origin of neurodegeneration in the nigrostriatal system is unclear, there is a general consensus that certain mechanisms are involved in the loss of neuromelanin-containing dopaminergic neurons.
They are related to the appearance of motor symptoms and involve oxidative stress, mitochondrial dysfunction, aggregation of alpha-synuclein to neurotoxic oligomers, dysfunction of both lysosomal and proteasomal protein degradation systems, endoplasmic reticulum stress, and neuroinflammation.
During these five decades since L-dopa wasintroduced in the palliative treatment of Parkinson's disease, a series of clinical studies have been carried out based on successful evidence obtained from preclinical models based on exogenous neurotoxins 6-hydroxydopamine and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).
The problem is that these successful preclinical studies have failed in advanced phases of clinical studies. These failed clinical studies include drugs such as coenzyme Q10 (PMID:24664227; mitoquinone (PMID:20568096); Isradipine (PMID: 32227247); creatine (PMID:25668262); nilotinib (PMID:33315105); urate (PMID: 34519802); Neurturin (PMID: 26061140);TCH346 (PMID: 17110281) and others.
In my opinion, the reason of the failure of these clinical studies are:
(i) the use of preclinical models that do not represent what happens in idiopathic Parkinson's disease.
Preclinical studies were performed with exogenous neurotoxins such as 6-hydroxydopamine and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) which induce a massive, propagative and extremely rapid degenerative process in animals.
In humans, MPTP induces severe Parkinsonism in only three days in drug addicts who used illicit drugs contaminated with MPTP.
This contrasts with the extremely slow degenerative process of idiopathic Parkinson's disease.
It takes years to reach 60% degeneration of the neuromelanin-containing dopaminergic neurons of the nigrostriatal system when motor symptoms appear, and from the onset of motorsymptoms to death, 15-20 years can pass. Recently, it was found that human substantia nigra pars compacta has between 800,000 to 1,000,000 neuromelanin-containing dopaminergic neurons in both hemispheres.
This implies that a patient with idiopathic Parkinson's has some 320,000 to 400,000 neuromelanin-containing dopaminergic neurons after the onset of motor symptoms and if the patient survives 15 years the patient would lose between 58-73 of these neurons daily.
This suggests that the degenerative process is extremely slow and the effect of drugs such as the antioxidant coenzyme Q10 used in these clinical studies probably neutralizes the oxidative stress generated in these 58 -73 neurons that degenerate daily but is imperceptible to the methodology used to measure significant effects in these clinical studies;
(ii) This antioxidant was possibly effective in neutralizing the oxidative stress of these 58-73 neurons that degenerate per day, but this drug did not prevent another 58-73 new neurons from degenerating the next day, because preclinical studies did not include the neurotoxin that triggered the mechanisms involved in the degenerative process such as mitochondrial dysfunction, endoplasmic reticulum stress, alpha-synuclein aggregation to neurotoxic oligomers, oxidative stress, dysfunction of both lysosomal and proteasomal protein degradation systems, and neuroinflammation.
The extremely rapid degeneration induced by MPTP in drug addicts suggests that the degenerative process of idiopathic Parkinson's disease is a model of single-neuron degeneration while slowly accumulating over time, where there is neither an expansive nor massive degenerative process that is induced by an endogenous neurotoxin, which is generated underc ertain conditions within neuromelanin-containing dopaminergic neurons. This would explain the extremely slow degenerative process observed in idiopathic Parkinson's disease.
The endogenous neurotoxin that is formed under certain conditions during neuromelanin synthesis within neuromelanin-containing dopaminergic neurons is aminochrome, which is neurotoxic by inducing mitochondrial dysfunction, endoplasmic reticulum stress, alpha-synuclein aggregation to neurotoxic oligomers, oxidative stress, dysfunctionof both lysosomal and proteasomal protein degradation systems, and neuroinflammation.
Aminochrome is a transient neurotoxin that in in vitro experiments with NMR is stable for 40 min but within dopaminergic neurons aminochrome is surrounded by proteins with which it can form adducts such as alpha-synuclein, actin, alpha- and beta-tubulin or it can be reduced by flavoenzymes that use NADH and NADPH as electron donors. Therefore, aminochrome does not have an expansive effect but induces the death of only one single-neuron at a time.
The endogenous neurotoxin aminochrome is formed during the synthesis of neuromelanin. However, neuromelanin synthesis is a normal and harmless process since neuromelanin-containing dopaminergic neurons are intact in healthy older adults.
This is explained because there are two enzymes that prevent the neurotoxic effects of aminochrome.
These enzymes that prevent the neurotoxic effects of aminochrome are DT-diaphorase, which is expressed in both dopaminergic neurons and astrocytes while glutathione transferase M2-2 is expressed only in astrocytes.
Interestingly, astrocytes secrete exosomes loaded with M2-2 glutathione transferase that transport this enzyme from astrocytes into dopaminergic neurons to increase their protection against the neurotoxic effects of aminochrome.
Therefore, preclinical studies should be based on the search for compounds that increase the expression of DT-diaphorase and glutathione transferase M2-2 through the transcriptional geneactivation via KEAP1/NRF2.
Although the origin of neurodegeneration in the nigrostriatal system is unclear, there is a general consensus that certain mechanisms are involved in the loss of neuromelanin-containing dopaminergic neurons.
They are related to the appearance of motor symptoms and involve oxidative stress, mitochondrial dysfunction, aggregation of alpha-synuclein to neurotoxic oligomers, dysfunction of both lysosomal and proteasomal protein degradation systems, endoplasmic reticulum stress, and neuroinflammation.
During these five decades since L-dopa wasintroduced in the palliative treatment of Parkinson's disease, a series of clinical studies have been carried out based on successful evidence obtained from preclinical models based on exogenous neurotoxins 6-hydroxydopamine and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).
The problem is that these successful preclinical studies have failed in advanced phases of clinical studies. These failed clinical studies include drugs such as coenzyme Q10 (PMID:24664227; mitoquinone (PMID:20568096); Isradipine (PMID: 32227247); creatine (PMID:25668262); nilotinib (PMID:33315105); urate (PMID: 34519802); Neurturin (PMID: 26061140);TCH346 (PMID: 17110281) and others.
In my opinion, the reason of the failure of these clinical studies are:
(i) the use of preclinical models that do not represent what happens in idiopathic Parkinson's disease.
Preclinical studies were performed with exogenous neurotoxins such as 6-hydroxydopamine and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) which induce a massive, propagative and extremely rapid degenerative process in animals.
In humans, MPTP induces severe Parkinsonism in only three days in drug addicts who used illicit drugs contaminated with MPTP.
This contrasts with the extremely slow degenerative process of idiopathic Parkinson's disease.
It takes years to reach 60% degeneration of the neuromelanin-containing dopaminergic neurons of the nigrostriatal system when motor symptoms appear, and from the onset of motorsymptoms to death, 15-20 years can pass. Recently, it was found that human substantia nigra pars compacta has between 800,000 to 1,000,000 neuromelanin-containing dopaminergic neurons in both hemispheres.
This implies that a patient with idiopathic Parkinson's has some 320,000 to 400,000 neuromelanin-containing dopaminergic neurons after the onset of motor symptoms and if the patient survives 15 years the patient would lose between 58-73 of these neurons daily.
This suggests that the degenerative process is extremely slow and the effect of drugs such as the antioxidant coenzyme Q10 used in these clinical studies probably neutralizes the oxidative stress generated in these 58 -73 neurons that degenerate daily but is imperceptible to the methodology used to measure significant effects in these clinical studies;
(ii) This antioxidant was possibly effective in neutralizing the oxidative stress of these 58-73 neurons that degenerate per day, but this drug did not prevent another 58-73 new neurons from degenerating the next day, because preclinical studies did not include the neurotoxin that triggered the mechanisms involved in the degenerative process such as mitochondrial dysfunction, endoplasmic reticulum stress, alpha-synuclein aggregation to neurotoxic oligomers, oxidative stress, dysfunction of both lysosomal and proteasomal protein degradation systems, and neuroinflammation.
The extremely rapid degeneration induced by MPTP in drug addicts suggests that the degenerative process of idiopathic Parkinson's disease is a model of single-neuron degeneration while slowly accumulating over time, where there is neither an expansive nor massive degenerative process that is induced by an endogenous neurotoxin, which is generated underc ertain conditions within neuromelanin-containing dopaminergic neurons. This would explain the extremely slow degenerative process observed in idiopathic Parkinson's disease.
The endogenous neurotoxin that is formed under certain conditions during neuromelanin synthesis within neuromelanin-containing dopaminergic neurons is aminochrome, which is neurotoxic by inducing mitochondrial dysfunction, endoplasmic reticulum stress, alpha-synuclein aggregation to neurotoxic oligomers, oxidative stress, dysfunctionof both lysosomal and proteasomal protein degradation systems, and neuroinflammation.
Aminochrome is a transient neurotoxin that in in vitro experiments with NMR is stable for 40 min but within dopaminergic neurons aminochrome is surrounded by proteins with which it can form adducts such as alpha-synuclein, actin, alpha- and beta-tubulin or it can be reduced by flavoenzymes that use NADH and NADPH as electron donors. Therefore, aminochrome does not have an expansive effect but induces the death of only one single-neuron at a time.
The endogenous neurotoxin aminochrome is formed during the synthesis of neuromelanin. However, neuromelanin synthesis is a normal and harmless process since neuromelanin-containing dopaminergic neurons are intact in healthy older adults.
This is explained because there are two enzymes that prevent the neurotoxic effects of aminochrome.
These enzymes that prevent the neurotoxic effects of aminochrome are DT-diaphorase, which is expressed in both dopaminergic neurons and astrocytes while glutathione transferase M2-2 is expressed only in astrocytes.
Interestingly, astrocytes secrete exosomes loaded with M2-2 glutathione transferase that transport this enzyme from astrocytes into dopaminergic neurons to increase their protection against the neurotoxic effects of aminochrome.
Therefore, preclinical studies should be based on the search for compounds that increase the expression of DT-diaphorase and glutathione transferase M2-2 through the transcriptional geneactivation via KEAP1/NRF2.