Parkinson’s disease, which affects more than 10 million people worldwide—including 200,000 in France—is a neurodegenerative disorder caused by the gradual loss of dopamine-producing neurons, a molecule essential for controlling our movements.
At the heart of this cellular dysfunction lies a protein called alpha-synuclein. In a healthy brain, it plays a protective role. But in Parkinson’s disease, it accumulates in a toxic, aggregated form, forming clumps called Lewy bodies, which literally kill neurons.
For a long time, one question has puzzled scientists: how can we explain the increase in this toxic, aggregated form observed in patients’ brains?
Our team, in collaboration with researchers from Marie-Christine Chartier Harlin’s group, has discovered a key mechanism that could explain this accumulation.
It all hinges on the dysfunction of another key protein in Parkinson’s disease: parkin. This protein performs multiple functions. It acts both as a “tagger” to mark proteins that the cell must dispose of (which are then recycled) and as a regulator of the activity of certain genes.
We have demonstrated that the malfunction of parkin could be responsible for the accumulation of the toxic form of alpha-synuclein through two different pathways.
One is direct, through parkin’s action on the alpha-synuclein gene.
The other is indirect, through parkin’s control of the degradation of alpha-synuclein by another enzyme, called beta-1 glucocerebrosidase. Here again, inactivation of parkin leads to a decrease in the expression of the glucocerebrosidase gene (it is also known that mutations in this gene are the most common genetic risk factor for Parkinson’s disease).
Finally, parkin works in concert with beta-1 glucocerebrosidase to regulate the components of a key cellular protein recycling pathway called “chaperone-mediated autophagy” (CMA; chaperones are proteins that “assist” other proteins).
In short, when parkin malfunctions—due to mutations or increased oxidative stress associated with aging (the stress caused to cellular components by oxidizing molecules produced by normal metabolism)—the entire system breaks down:
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the production of physiological (protective) alpha-synuclein decreases (due to a reduction in the expression of its gene);
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its breakdown is also blocked, leading to the accumulation of its toxic form.
How was this discovery made possible?
We used and cross-referenced results obtained at the cellular, animal, and human sample levels (postmortem brain samples and fibroblasts—connective tissue cells found primarily in the dermis—from patients with parkin mutations).
Research on cell lines capable of overproducing or underproducing parkin allowed us to demonstrate the regulation of the alpha-synuclein and beta-1 glucocerebrosidase genes. We were also able to show that parkin is capable of interacting with regions important for gene expression and that it influences key factors responsible for chaperone-mediated autophagy.
Studies in transgenic animals that do not produce parkin, meanwhile, allowed us to corroborate our findings.
Finally, the findings obtained from patient samples allowed us to validate the relevance of our results in humans.
Why is this discovery important?
The scientific impact of our findings is multifaceted. They demonstrate a major role for parkin in gene regulation, particularly through its as-yet-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 the alpha-synuclein and beta-1 glucocerebrosidase genes, as well as in chaperone-mediated autophagy, was previously unknown.
Our data bring together previously disparate observations (the roles of parkin, beta-1 glucocerebrosidase, and chaperone-mediated autophagy) into a coherent model applicable to both hereditary and sporadic forms of the disease.
What are the implications of this research?
Chaperone-mediated autophagy is an essential cellular recycling pathway specialized in the removal of soluble proteins such as alpha-synuclein.
The fact that parkin is involved in regulating this process opens up significant possibilities regarding the scope 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 reactivating chaperone-mediated autophagy, the protein recycling process that is impaired in Parkinson’s disease.
Finally, these discoveries point to applications that extend beyond the context of Parkinson’s disease alone, as parkin is involved in other brain disorders, such as Alzheimer’s disease and brain cancers.
Our “Research Briefs” are designed to provide a three-minute overview of recent research findings, explained and put into context by the researchers who conducted the studies. You can find this format here.
Cristine Alves Da Costa is a faculty member and researcher at the Institute of Molecular and Cellular Pharmacology (Université Côte d’Azur, CNRS).
This article is republished from The Conversation under a Creative Commons license. Read the original article.
