Parkinson’s is the second most common neurodegenerative disease after Alzheimer’s and it is estimated that seven million people worldwide and around 160,000 people in Spain suffer from it, according to data from the Spanish Parkinson’s Federation. Now, an unprecedented investigation led by Patricia Gonzalez-Rodrigueza scientist from Arcos de la Frontera (Cádiz) at Northwestern University, has identified one of the causes of the progression of Parkinson’s in the brain, which will help to develop new treatments to combat this pathology.
The results of the study, which has been published in Nature, show how defects in mitochondrial complex 1 in the brain, which are needed for dopamine-producing neurons to survive, and whose absence or abnormal functioning causes their destruction, generate the progression of Parkinson’s, slowly but steadily. This discovery has also made it possible to identify therapeutic targets to stop, and even reverse, the disease.
José López Barneo, Professor of Physiology at the Faculty of Medicine of Seville and IBiS researcher and co-author of the research, explained that Parkinson’s is caused by the “death of many neurons, but especially the most important ones, those of the gray matter of the brain that generate dopamine”, which is a key neurotransmitter that intervenes in the motor function of the organism. This neuronal death results in the appearance of tremors and rigidity that constitute the first symptoms of Parkinson’s: “the characteristic motor syndrome of the disease”.
Parkinson’s is caused by the “death of many neurons but, especially, the most important, those of the gray matter of the brain that generate dopamine”
This expert adds that “mitochondria had long been associated with [los orgánulos responsables de la respiración celular, las plantas energéticas del cuerpo] with Parkinson’s, but the pathogenesis, the causes of the disease, how it occurs and how neurons die, is not well understood. “Discovering it,” he continues, “can lead to medications that go to the cause of the disease, not just the symptoms.”
Patricia González-Rodríguez, trained at the University of Seville, and who continued at Northwestern University in Chicago the career she began at the Institute of Biomedicine of Seville (IBiS), indicates that “the absence of an adequate model to test this hypothesis has generated confusion in the field of Parkinson’s, not knowing if defects in mitochondrial complex 1 were the cause or consequence of the disease. But the research she leads demonstrates this for the first time, and determines that dysfunction in this area of the brain occurs first.
New options to treat and reverse Parkinson’s
To carry out the research, a murine model (mouse) has been used in which the Ndufs2 gene has been selectively eliminated –which is key to the formation of mitochondrial complex 1– in order to analyze the impact that its suppression had on the black substance. The researchers found that its absence triggered progressive Parkinson’s with characteristics similar to that developed by a person suffering from dysfunction in the complex.
López Barneo points out that “this model shows, for the first time, that complex 1 is absolutely necessary for the survival of these neurons and that its absence produces their progressive destruction, not abruptly, but over several weeks or months. It is very similar to the course of the disease that occurs in humans.” González-Rodríguez adds: “To date, it is the first animal model known to mimic Parkinson’s in people”, which was genetically modified in 2015 at IBiS.
“Dopaminergic neurons affected by Parkinson’s disease lose some of their properties, but they do not die for a long time, that is, they could reactivate (recover)”
As explained by the Andalusian scientist, the disease first affects the neurons that produce dopamine, the axon, the long, thin structure that transmits the electrochemical impulse to another nerve cell. They then alter the soma, the spherical cell body that contains the nucleus. The finding is important because, as González-Rodríguez clarifies: “For more than 30 years, the prevailing opinion has been that the cardinal motor symptoms of Parkinson’s are caused by the depletion of dopamine in the axons. However, we conclude that a lack of dopamine in the soma is also necessary for parkinsonism (abnormal movements) to occur”.
The investigation of the process is also relevant because, according to López Barneo, “neurons do not die when this complex fails, but begin to malfunction”: “They remain alive due to adaptive mechanisms, but with changes in their function that give rise to a series of changes that appear over time. This opens the way to new therapeutic approaches because, according to López Barneo, “neurons are potentially salvageable before they end up dying and there is a very wide window for therapy there. It could be reversible at some point.”
González-Rodríguez specifies that “the dopaminergic neurons affected by Parkinson’s disease lose some of their properties and change their metabolism, but they do not die for a long time, that is, they could reactivate (recover), contrary to what was thought until now”. The results of the study therefore expand the possibilities of using new tools and compounds to stop or slow down the progression of this neurodegenerative disease and reverse its effects.
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