Speakers - 2026

One of the biggest problems in the field of idiopathic Parkinson's disease is the failure to discover new drugs that halt or slow the progression of the disease. Fifty-nine years after the introduction of L-Dopa for Parkinson's treatment, it remains the gold standard despite the severe side effects that appear after four to six years of chronic treatment.

There is a long list of failed clinical trials based on successful preclinical studies using exogenous neurotoxins such as MPTP and 6-hydroxydopamine. The question is, why have these clinical trials failed? In my opinion, these clinical trials have failed because they are based on preclinical models that do not accurately represent the neurodegenerative process in idiopathic Parkinson's disease. These exogenous neurotoxins induce a very rapid and expansive neurodegenerative process, while the neurodegenerative process in idiopathic Parkinson's disease is extremely slow. It takes years before motor symptoms of the disease appear, and then it can take between 10 and 20 years for the disease to progress until the patient dies. MPTP induces severe parkinsonism in as little as 3 days. This suggests that the neurotoxin that triggers the neurodegenerative process in idiopathic Parkinson's disease is of endogenous origin, inducing mitochondrial dysfunction, formation of neurotoxic oligomers, dysfunction of both lysosomal and proteasomal protein degradation systems, endoplasmic reticulum stress, neuroinflammation, and oxidative stress.

It has been proposed that the endogenous neurotoxin that induces all the aforementioned neurotoxic mechanisms are generated during neuromelanin synthesis. Aminochrome is an ortho-quinone, one of the three ortho-quinones that are transiently generated during neuromelanin synthesis and is also the most stable. An important characteristic of aminochrome is that (i) it is formed within neuromelanin- containing dopaminergic neurons in the nigrostriatal system during Parkinson's disease; (ii) it does not induce propagating neurotoxic effects, implying that it only affects a single neuron.

Neuromelanin synthesis is a normal and harmless event, as older adults have intact neuromelanin- containing dopaminergic neurons at the time of death. This is explained by the existence of two enzymes (DT-diaphorase and glutathione transferase M2-2) that prevent the neurotoxic effects of aminochrome within neuromelanin-containing dopaminergic neurons. The loss of neuromelanin-containing dopaminergic neurons is an extremely slow process in which there is no massive loss of these neurons due to a propagating effect of the neurotoxin that triggers the neurotoxic mechanisms described above. There is no isolated loss of neurons that accumulate over time, reaching up to 60% when the motor symptoms of the disease appear. Once diagnosed, the disease progresses for years until the patient's death. Therefore, the mechanism of action of the endogenous neurotoxin aminochrome when the neuroprotective action of DT-diaphorase and glutathione transferase M2-2 fails or is exceeded resembles the action of the endogenous neurotoxin that triggers the neurodegenerative process in idiopathic Parkinson's disease. We have therefore proposed that the neurodegeneration of the dopaminergic system containing neuromelanin in the nigrostriatal system is governed by a single-neuron degeneration model.