NewsTHE CONVERSATION: Parkinson's: Advances in understanding a key molecule of the disease
About
Link to the article:
We know that Parkinson's disease, which affects more than 10 million people worldwide, including 200,000 in France, is a neurodegenerative disease due to the progressive disappearance of neurons that produce dopamine, a molecule essential for controlling our movements.
At the heart of this cellular dysfunction lies a protein, alpha-synuclein. In a healthy brain, it plays a protective role. But in Parkinson's disease, it accumulates in a toxic and aggregated form, forming clumps called Lewy bodies., which literally kill neurons.
For a long time, scientists have been puzzled by one question: how to explain the increase in its aggregated toxic form observed in the brains of patients?
Our team, in collaboration with researchers from the team of Marie-Christine Chartier Harlin, discovered a key mechanism that could explain this accumulation.
Everything hinges on the malfunction of another key protein in Parkinson's disease: parkin. This protein is multitasking. It acts as both a labeling machine for marking proteins which the cell must get rid of (these are then recycled) and like a regulator of the activity of certain genes.
We have demonstrated that Parkin failure could be the cause of the accumulation of the toxic form of alpha-synuclein, by two different routes.
Every Tuesday in "And Above All, Health", a wealth of information: nutrition, well-being, new treatments…
This site is protected by reCAPTCHA and the Google Privacy Policy. Privacy Policy and the terms of service apply.
One is direct, through the action of parkin on the alpha-synuclein gene.
The other is indirect, through the control by parkin of the degradation of alpha-synuclein by another enzyme, called glucocerebrosidase beta 1. Here again, the inactivation of parkin causes a decrease in the expression of the glucocerebrosidase gene (it is also known that mutations of this gene are the most common genetic risk factor for Parkinson's disease).
Finally, parkin acts in concert with glucocerebrosidase beta 1 to regulate the components of an essential pathway of cellular protein recycling called "chaperone protein-mediated autophagy" (or CMA, for Chaperone-Mediated Autophagy ; (Chaperones being proteins that "help" other proteins).
In short, when parkin malfunctions, due to mutations or increased oxidative stress related to aging (stress caused to cell components by oxidizing molecules produced by normal metabolism), the entire system seizes up:
- the production of physiological (protective) alpha-synuclein decreases (due to the decrease in the level of its gene);
- Its degradation is also blocked, leading to the accumulation of its toxic form.
How was this discovery made possible?
We used and cross-referenced the results obtained at the cellular, animal and human sample level (post-mortem brain samples and fibroblasts – connective tissue cells present in particular in the dermis – from patients carrying parkin mutations).
Work on cell lines capable of overproducing or underproducing parkin has allowed us to highlight the regulation of alpha-synuclein and glucocerebrosidase beta 1 genes. We have also been able to show that parkin is capable of interacting with regions important for gene expression, and that it has an impact on key players responsible for chaperone-mediated autophagy.
Studies in transgenic animals that do not produce parkin have, for their part, allowed us to corroborate our results.
Finally, the results obtained from samples taken from patients allowed us to validate the relevance of our results in humans.
Why is this discovery important?
The scientific impact of our results is multifaceted. They demonstrate a major role for parkin in gene regulation, particularly through its still little-explored function as a transcription factor.
Until now, it was known that parkin played a role in the degradation of multiple proteins, but its involvement in the transcription of alpha-synuclein genes, glucocerebrosidase beta 1 and in chaperone-mediated autophagy was previously unknown.
Our data unify previously disjointed observations (role of parkin, glucocerebrosidase beta 1 and chaperone-mediated autophagy) into a coherent model, applicable to hereditary and sporadic forms of the disease.
What are the prospects for this work?
Chaperone-mediated autophagy is an essential cellular recycling pathway specialized in the elimination of soluble proteins such as alpha-synuclein.
The fact that parkin participates in the regulation of this process opens up important perspectives regarding the extent of its biological functions and its therapeutic potential.
One avenue of research is now to identify new molecules capable of restoring parkin function. A second approach will be to develop specific activators capable of restarting chaperone-mediated autophagy, the protein recycling process that malfunctions in Parkinson's disease.
Finally, these discoveries suggest applications that go beyond the context of Parkinson's disease alone, because parkin is involved in other brain disorders, such as Alzheimer's disease or brain cancers.