Authors: Nerea Larrañaga and Paula Marco
Scientists from the International Parkinson and Movement Disorders Society (MDS) have published a paper highlighting the main research priorities for the α-synuclein (αSyn) protein in Parkinson's disease. This review, led by an international team of experts, focuses on addressing key issues that remain unresolved after more than 25 years of research on this protein, whose aggregation is a central feature of Parkinson's, both in its sporadic and genetic (familial or inherited form). However, understanding of its role in the evolution and pathogenesis of the disease remains limited.
The importance of α-synuclein in Parkinson's disease
αSyn is a small protein that accumulates in the neurons of people affected by Parkinson's, forming inclusions or clumps known as Lewy bodies, which is considered one of the key markers of the disease, as it is a unique feature of the disease. Although mutations in the SNCA gene (the gene from which αSyn is produced) and duplication or triplication of this gene are associated with familial cases of Parkinson's, the exact role of αSyn in the development of the disease is not yet fully understood. One of the most important debates is whether the accumulation of αSyn is directly toxic to neurons or whether it is a side effect of other pathological processes.
Accordingly, the MDS scientific committee has identified six key questions on which research should focus.
- What are the physiological functions of α-synuclein?
It has been observed that loss of function of α-synuclein, i.e. its loss due to the formation of clumps as in Parkinson's disease patients, does not directly cause neurodegeneration, but its abnormal accumulation is linked to the deterioration of neurons. In addition, this protein is also involved in the regulation of neurotransmitter release, but its exact role in this process and how its mutations contribute to Parkinson's disease remain important aspects that require further research.
Understanding the normal function and regulation of α-synuclein in its environment is crucial, not only to develop therapies that reduce the amount of total αSyn or favour physiological αSyn over its altered states, but also to understand the context in which the disease develops.
- What mechanisms trigger αSyn aggregation?
Researchers still do not fully understand what factors induce αSyn to clump together and form Lewy bodies. Some theories suggest that the accumulation of the protein is related to poor management of cellular stress (mechanisms by which cells deal with the waste generated in their normal activity), alterations in protein clearance or interactions with cell membrane lipids. In addition, we are exploring how genetic and environmental factors interact to facilitate the accumulation of α-synuclein and its conversion into toxic forms that damage cells.
- What is the distribution of αSyn in the brain?
Although Lewy bodies appear in specific areas of the brain in people with Parkinson's, it is unclear why some neurons are more vulnerable to this pathology than others. It has been suggested that the distribution of αSyn may be related to neuronal connectivity and activity patterns in certain brain regions, so future research should focus on more precisely mapping these brain connections and how neuron-specific factors influence the spread and toxicity of α-synuclein aggregates.
- How are αSyn aggregation and neuronal dysfunction related?
There is a strong correlation between α-synuclein aggregation and Parkinson's disease, but proving a direct causal link in humans remains a challenge, as one of the great mysteries of the disease remains how αSyn accumulation affects neuronal function. It has been proposed that αSyn accumulation may alter neurotransmitter release and damage mitochondria, which are essential for cellular energy supply, but more work is needed to understand how different conformations of the protein affect neurons.
- How does α-synuclein spread in the brain?
One of the most widely accepted hypotheses is that pathological αSyn behaves similarly to a prion, meaning that it can spread from cell to cell inducing its abnormal structure to other physiological αSyn, accelerating the spread of the pathology to different areas of the brain. However, there is an urgent need to develop reliable biomarkers that can detect and quantify pathological α-synuclein in living patients, which would allow more accurate monitoring of disease progression and the efficacy of therapies.
- Is there a possibility of rescuing affected neurons?
Finally, experts are exploring whether it is possible to intervene to save neurons that have accumulated αSyn before they die. Some regions of the brain appear to be able to withstand high αSyn loads without experiencing degeneration, and not all α-synuclein aggregates are equally toxic, opening up the possibility that certain interventions could protect affected brain cells or specifically target the most harmful altered forms of the protein.
The future of research and potential therapeutic breakthroughs
One of the main goals of the team of experts is to develop better experimental models that can replicate the different stages of the disease, from early αSyn accumulation to advanced neuronal dysfunction. The scientists propose the creation of new tools to study αSyn in its various forms (soluble, aggregated and oligomeric) to better understand how it interacts with other cellular components and how this leads to neuronal dysfunction.
Advances in technology, such as human brain cell culture models and the application of new imaging techniques to study the spread of αSyn in the brain, may offer new approaches to studying the pathogenesis of Parkinson's and designing therapeutic interventions. In addition, studies that integrate data from these models with information from clinical studies will provide a better understanding of how the disease begins and progresses in humans.
Conclusion
The paper stresses that a better understanding of αSyn and its role in the development of the disease is essential to advance the development of treatments to modify the progression of Parkinson's disease. Through new research that answers the key questions raised by the expert panel, scientists hope to design therapies that can slow or even reverse the progression of Parkinson's disease. This approach promises to shed light on one of the world's most prevalent and devastating neurodegenerative diseases, paving the way for more effective treatments in the future.
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