NewsTHE CONVERSATION: Parkinson's: Understanding how toxic proteins accumulate in neurons
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Currently, there is no cure for Parkinson's disease. The discovery of the long-overlooked function of a protein involved in the disease provides a better understanding of how it develops and could open up new therapeutic avenues.
Parkinson's disease continues to progress. It is estimated that by 2050 it will affect more than 25 million people worldwide, compared to 11.8 million in 2021. According to these assessments, the situation in France, which is among the ten most affected countries in the world, is not expected to improve.
This is hardly surprising: currently, there is no treatment capable of curing this condition. Available medications can only alleviate the symptoms experienced by patients. To have any hope of changing things, it is essential to better understand the mechanisms of the disease.
This is what my team and I are working on. Our research has revealed that a protein associated with the disease—parkin—is capable of interacting with DNA. Discovering this role sheds light on some of the disease's mechanisms and could lead to the identification of new therapeutic approaches.
The disease originates from a drop in dopamine production.
The increase in Parkinson's disease is due to both the aging population and improved diagnostic methods. The significant medical, social, and economic consequences of this condition make it a major public health issue. Currently, however, many questions remain unanswered regarding its causes.
We know that this condition originates in a region of the brain called the substantia nigra. This is where a particular type of neuron, called "dopaminergic neurons," is located. As their name suggests, they are responsible for the production of dopamine.
This molecule, which acts both as a neurotransmitter (a chemical messenger carrying information between nerve cells) and as a hormone, plays a central role in many processes. For example, it is involved in regulating pleasure and in the reward system. Dopamine is also very important for controlling movement, as well as for many other functions: motivation, learning, attention, emotional regulation, stress response, and cognitive functions.
When the neurons that produce it degenerate, its production drops, which is the cause of the motor symptoms of Parkinson's disease: tremors, slowness of movement, muscle rigidity. While these symptoms are well known, it is less known that the disease is also accompanied by so-called "non-motor" symptoms: loss of smell, constipation, depression, cognitive difficulties…
These are all signs that complicate the diagnosis and management of patients as their disease progresses. Early diagnosis is particularly important because, to slow the decline in patients' abilities as much as possible, available treatments must be administered as soon as possible. These treatments, as we will see, still have considerable room for improvement.
Treatments that need improvement
Current treatments primarily rely on the administration of L-DOPA, a dopamine precursor (that is, a molecule that, after modification, can be converted into dopamine). These medications can relieve symptoms, sometimes dramatically, but do not slow the progression of the disease.
To delve deeper, it is therefore essential to understand what happens inside neurons. To this end, researchers are studying various proteins. Within our team, we are working to elucidate the role of a trio of molecules, each of which plays a central role in the onset and progression of Parkinson's disease: parkin, alpha-synuclein, and glucocerebrosidase.
Our goal is to clarify how these three priority targets interact, in order to identify new therapeutic avenues for both sporadic and familial forms of the disease. To understand how these three proteins can lead to disease development, we must revisit the role they play within cells.
A new function for the parkin
Normally, alpha-synuclein is a beneficial protein, as it prevents the death of nerve cells. However, when it is mutated, chemically altered, or insufficiently eliminated, it accumulates in neurons, where it gradually forms toxic aggregates. These clumps, which disrupt neuronal function, are considered to be one of the major hallmarks of Parkinson's disease.
Why and how does alpha-synuclein accumulate? Our work, which focuses on parkin, another member of the aforementioned trio of proteins, opens up avenues to answer this question.
In nerve cells, parkin promotes the elimination of excess proteins. However, in 2009, we demonstrated that it also performs another function: it is also capable of control the expression of certain genes in cells.
This discovery overturned the established dogma that this protein performed a single, unique function. This has important implications for the development of Parkinson's disease.
A cascade of disruptions
When parkin is altered—due to mutations, aging, or other mechanisms—several cellular processes become disrupted. This is the case not only for the regulation of alpha-synuclein production, but also for that of the third member of our trio of proteins: glucocerebrosidase. Normally, this enzyme plays a crucial role in the degradation of alpha-synuclein (as well as other cellular compounds).
Currently, we are continuing our work, with the aim of estimating the role of parkin in the direct and indirect regulation of the alpha-synuclein gene.
If parkin no longer plays its role as a regulator of gene expression, the production of alpha-synuclein is disrupted, which leads to its aggregation (by various mechanisms that we will not explain here).
Furthermore, parkin inactivation leads to decreased expression of the glucocerebrosidase gene, thereby hindering the degradation processes involved in protein elimination. As a result, alpha-synuclein, in its aggregated and toxic form, accumulates in nerve cells (results pending publication).
Towards new therapeutic avenues
Our results highlight that the ability of parkin to control genes involved in the degradation of toxic proteins (via the regulation of glucocerebrosidase) is crucial.
This ability is not only involved in the development of Parkinson's disease, but also, probably, in other neurodegenerative diseases associated with dysfunctions of the cellular machinery responsible for protein degradation, for example Alzheimer's disease.
Ultimately, we hope to gain a better understanding of the gene regulation mechanisms of alpha-synuclein, as well as the role played by parkin in the development of genetic (linked to mutations in the gene of this protein) and sporadic forms of Parkinson's disease (the most widespread forms).
This knowledge could lead to the identification of new therapeutic approaches that address the causes of the pathology, and not just its symptoms.
The project SynaPark (ANR-20-CE16-0008) is supported by the French National Research Agency (ANR), which funds project-based research in France. The ANR's mission is to support and promote the development of basic and applied research in all disciplines, and to strengthen the dialogue between science and society. For more information, please visit the ANR website.’ANR.