A Study Reveals One of the Reasons Why Neurons Die in Parkinson’s Patients

Summary: Study implicates the gene DJ1 in neuronal death associated with Parkinson’s disease.

Source: University of Córdoba

Parkinson’s disease affects about 7 million people worldwide, according to data provided by the World Health Organization (WHO). This neurodegenerative disorder affects the central nervous system and, although its causes are not yet fully understood, it is known that many of its symptoms are due to the loss of neurons that produce dopamine.

A study carried out by a research team at the University of Cordoba has revealed, in mice, one of the reasons for this neuronal loss: the key lies in the protein called DJ1, whose relationship with Parkinson’s disease had already been demonstrated, although until now its exact function was unclear.

This study went a step further in this area, revealing one of this protein’s action mechanisms. To do this, the research team carried out a comparative study of neurons in the brains of mice that have this active gene, and others that lack it, with the aim of “comparing the differences between the two protein patterns and, thus, studying the mechanisms that may be altered,” explains Raquel Requejo, principal investigator of the study and a member of the BIO126 group at the University of Cordoba. 

When dividing is not an option

According to the results of the study, the absence or dysfunction of the gene expressing the DJ1 protein causes the activation of what is known as the cell cycle, the process by which cells divide; in other words, the machinery used by cells to replace others that have died, as occurs, for example, when a wound heals. 

This shows a head and a question mark
Parkinson’s disease affects about 7 million people worldwide, according to data provided by the World Health Organization (WHO). Image is in the public domain


What is the real problem here? The answer is that neurons do not have the capacity to divide,yet they ‘receive instructions’ to do so through the triggering of a cell cycle that, under normal conditions, should not occur. As a result, when a gene is altered, its neurons are forced into a division process that they are unable to complete and end up dying, thus producing many characteristic symptoms of Parkinson’s disease. 

This is what is known in the scientific literature as an “aberrant cell cycle” and its relationship “with this neurodegenerative disease and the absence of the DJ1 protein has been described for the first time in this study,” said Requejo. 

To date, Parkinson’s disease has no cure, per se, and current treatments consist of externally supplying the dopamine that the dying neurons stop producing naturally, explained the study’s lead author. In the future, this finding could favor the development of new therapeutic approaches that not only combat the symptoms but also prevent their cause, also behind other neurodegenerative diseases: neuronal death.

About this genetics and Parkinson’s disease research news

Author: Elena Lazaro
Source: University of Córdoba
Contact: Elena Lazaro – University of Córdoba
Image: The image is in the public domain

Original Research: Open access.
Deficiency of Parkinson’s Related Protein DJ-1 Alters Cdk5 Signaling and Induces Neuronal Death by Aberrant Cell Cycle Re-entry” by Raquel Requejo et al. Cellular and Molecular Neurobiology


Abstract

Deficiency of Parkinson’s Related Protein DJ-1 Alters Cdk5 Signaling and Induces Neuronal Death by Aberrant Cell Cycle Re-entry

DJ-1 is a multifunctional protein involved in Parkinson disease (PD) that can act as antioxidant, molecular chaperone, protease, glyoxalase, and transcriptional regulator. However, the exact mechanism by which DJ-1 dysfunction contributes to development of Parkinson’s disease remains elusive.

Here, using a comparative proteomic analysis between wild-type cortical neurons and neurons lacking DJ-1 (data available via ProteomeXchange, identifier PXD029351), we show that this protein is involved in cell cycle checkpoints disruption.

We detect increased amount of p-tau and α-synuclein proteins, altered phosphoinositide-3-kinase/protein kinase B (PI3K/AKT) and mitogen-activated protein kinase (MAPK) signalling pathways, and deregulation of cyclin-dependent kinase 5 (Cdk5). Cdk5 is normally involved in dendritic growth, axon formation, and the establishment of synapses, but can also contribute to cell cycle progression in pathological conditions.

In addition, we observed a decrease in proteasomal activity, probably due to tau phosphorylation that can also lead to activation of mitogenic signalling pathways.

Taken together, our findings indicate, for the first time, that aborted cell cycle re-entry could be at the onset of DJ-1-associated PD.

Therefore, new approaches targeting cell cycle re-entry can be envisaged to improve current therapeutic strategies.

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  1. The title of the Neuroscience News article was extremely misleading: “A Study Reveals One of the Reasons Why Neurons Die in Parkinson’s Patients.” The study was done in cell culture, so no comment can be made on what happens in an intact organism, much less Parkinson’s Patients. Also, from the abstract, it is not clear to me that they looked for or found differences in neuronal death between the two lines.

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