Researchers from the http://en.vhir.org/portal1/grup-equip.asp?s=recerca&contentid=186912 Neurodegenerative Diseases Group of the Vall d'Hebron Research Institute (VHIR), led by Dr. Miquel Vila, have managed to establish for the first time a functional link between the intracellular levels of the neuronal pigment neuromelanin and the dysfunction of dopaminergic neurons leading to Parkinson's disease. Thus, the researchers have observed that the progressive accumulation of neuromelanin, that occurs with aging eventually cause the dysfunction and degeneration of these neurons and when it exceeds a certain threshold, gives rises to the typical characteristics of Parkinson's Disease. In addition, the researchers have shown that modulating the neuromelanin levels below this pathological threshold can prevent the onset of the disease in an experimental model. This is described in an article published in the journal https://www.nature.com/articles/s41467-019-08858-y Nature Communications.Parkinson's disease is caused by the loss of neurons in a region called the black substance of the brain, responsible for the production of dopamine and, among other functions, the regulation of the voluntary movement. The dopamine deficit in brain regions innervated by these regions causes the appearance of the motor symptoms characteristic of the disease. With age, which is the main risk factor for developing Parkinson's disease, the dopaminergic neurons of the black substance are progressively accumulating a pigment called neuromelanin, similar to skin melanin and that it can reach all of the neuron, giving the black substance of the brain the dark brown appearance that its name indicates. Since 1919, a hundred years ago, it was known that the neurons containing neuromelanin are those that degenerate preferentially in Parkinson's disease. In spite of this, the possible role of neuromelanin in Parkinson's disease has remained unknown to date, since, unlike humans, the animals of experimentation used in the laboratory do not have neuromelanin. To overcome this obstacle. The VHIR researchers have developed, using genetic manipulation, the first experimental animal model that produce and accumulate neuromelanin with age in human-like quantities. Animal model with neuromelaninIt is known that neuromelanin is produced from the dopamine but, since the synthesis route of skin melanin is well studied, the neuromelanin formation mechanisms in the brain are still unknown. On the skin, the melanin is formed by the action of the tyrosinase enzyme. This enzyme is also found in the brain, in low quantities but it was not known if it had any role in the neuromelanin synthesis. The researchers over-expressed the tyrosine in the black substance of rodents (rat and mouse) and observed that these animals, which normally do not have neuromelanin, began to produce it and that it accumulated progressively with age until to reach levels equivalent to aged human brains, reaching all the entire neuron. These animals represent the first experimental model in rodents that produces and accumulates neuromelanin equivalent to humans. With this new animal model, the researchers could now answer the question of whether the progressive accumulation of neuromelanin in the interior of the neuron can affect the normal functioning of the cell.Pathological threshold of intracellular accumulation of neuromelanin"Using this new animal model of neuromelanin production, we observed that, based on a certain threshold of intracellular level of this pigment, the neurons began to present functional alterations and degeneration, so that these animals ended up developing the typical characteristics, motors and neuropathological, of Parkinson's disease" explains Dr. Miquel Vila, ICREA researcher and head of the Neurodegenerative Diseases group of the VHIR and the CIBER of Neurodegenerative Diseases (CIBERNED).To verify whether this observation could be transferred to humans, the researchers measured the levels of intracellular neuromelanin in healthy aged human brains and aged brains of Parkinson's patients. In the elderly, non-Parkinson's brain cells the levels of intracellular neuromelanin are below the pathological threshold, On the other hand, in the brain with Parkinson's, neurons already have levels of neuromelanin above this threshold. "We even verified that in brains of pre-Parkinson's individuals, that is, in very early phases of the disease in which symptomatology is not yet manifest but in which there are already neuropathological alterations, the accumulation of neuromelanin is already above the pathological threshold, suggesting that if these people had lived longer, they would probably have developed Parkinson's disease," he adds.Therapeutic modulation of the intracellular levels of neuromelanin To determinate if the modulation of neuromelanin levels could be beneficial, the researchers applied a gene therapy strategy to activate the recycling and elimination of residues that are characteristic of the neuron in their animal model. "With this strategy, we were able to reduce the intracellular levels of neuromelanin below the pathological threshold and prevent the appearance of the symptoms and neurodegeneration in these animals" says Dr. Vila, who is also professor at the Department of Biochemistry and Molecular Biology of the Autonomous University of Barcelona (UAB).These results of the study, in which researchers from the Institute of Biomedical research August Pi i Sunyer (IDIBAPS) also participated, indicate that the modulation of the neuromelanin levels below the pathological threshold could represent a new therapeutic strategy for the Parkinson's disease. Since all humans accumulate neuromelanin with age and therefore potentially end up developing Parkinson's disease if they lived sufficiently, this strategy could also be applied to modulate neuromelanin levels during the cerebral aging of the general population Reference: Carballo-Carbajal I*, Laguna A*, Romero-Gimenez J, Cuadros T, Bové T, Martinez-Vicente M, Parent A, Gonzalez-Sepulveda M, Peñuelas N, Torra A, Rodriguez-Galvan B, Ballabio A, Hasegawa T, Bortolozzi A, Gelpi E, Vila M. Brain tyrosinase overexpression implicates age-dependent neuromelanin production in Parkinson's disease pathogenesis. Nature Communications (2019)