Parkinson’s disease is a neurodegenerative disorder that affects between one and four percent of people between 65 and 85 years of age. Currently, no treatment is able to stop or reduce the progression of the disease, so it is necessary to develop therapies with new approaches that improve and control its symptoms.

Through the work of cell biologists, focused on studying transcription factors, information has been generated that opens up the possibility of new treatments for Parkinson’s disease that seek to increase the levels of a ubiquitinating enzyme called parkin.

The loss of the functionality of this protein, through genetic or environmental causes, is an important factor for the development of both autosomal juvenile Parkinson’s disease and the idiopathic type.

Guillermo Elizondo Azuela, assigned to the Department of Cell Biology of the Center for Research and Advanced Studies (CINVESTAV) and head of the research, has studied for years the physiological role of a transcription factor known as aryl hydrocarbons receptor (AHR).

AHR has been studied as a toxic mediator of some compounds such as dioxins, which are produced when organic material are burned or in the manufacture of pesticides. Recently, the Elizondo Azuela research group discovered that when activating AHR in cell, dioxins promote transcription of the parkin coding gene.

If this ubiquitinating enzyme does not work properly, the cell accumulates proteins that had to be degraded, which translates into cell death. In particular, when this occurs in dopaminergic neurons, dopamine levels decreased –a neurotransmitter that performs several functions, including movement modulation. Although it is not the only factor, parkin dysfunction is related to the development of neurodegenerative disorder,” said the CINVESTAV researcher.

In addition, parkin has a significant role in maintaining mitochondrial quality; so if lost, oxidative stress is increased, affecting dopaminergic neurons. Likewise, that enzyme can inhibit neuronal death by blocking the exitotoxicity produced by a neurotransmitter known as glutamate.

The above points to parkin as a neuroprotective agent; and the induction of its expression could be a strategy for the prevention and treatment of neurodegenerative diseases. In fact, some research groups, through the use of viral agents, have managed to overexpress the enzyme in the brain of rats, giving them a neuroprotection to some neurotoxic agents associated with the development of Parkinson’s disease.

Therefore, CINVESTAV scientists focused on analyzing the pathways that induce the genetic expression of parkin from the activation of AHR. “We analyzed whether AHR was expressed in several regions of the brain, and we found that, among others, it is present in the ventral mescencephalon, that is, in the area where dopaminergic neurons are found. We evaluated whether the activation of AHR by treatment with tetrachlorodibenzo-p-dioxin (TCDD) promoted the overexpression of parkin in the mouse midbrain. The results were positive, the activation of AHR caused an increase in parkin levels in the brains of mice,” said Elizondo Azuela.

While TCDD is a highly toxic compound, which rules out its use in humans, there are other harmless AHR ligands such as some tryptophan derivatives. There are even commonly used medications on the market, such as omeprazole, which have the ability to activate AHR.

These results suggest that therapies designed to induce parkin expression, through the use of agonist ligands of AHR, could be a novel strategy in preventing or delaying the onset of neurodegenerative diseases such as Parkinson’s disease.

 

Source: Conexion Cinvestav