Researchers at the Scripps Research Institute in Florida have developed a novel method to combat the levels of α-synuclein protein, a key contributor to Parkinson’s disease. By targeting the mRNA that forms this protein, the researchers have opened up new avenues for potential therapeutic approaches in the treatment of neurodegenerative diseases.
The study, titled “Decreasing the Intrinsically Disordered Protein α-Synuclein Levels by Targeting its Structured mRNA with a Ribonuclease-Targeting Chimera,” was published in the Proceedings of the National Academy of Sciences (PNAS). The team introduced two tools called Synucleozid-2.0 and Syn-RiboTAC, which are a duo capable of binding to and degrading the mRNA responsible for producing α-synuclein. This approach allows for the modulation of α-synuclein, a protein traditionally considered “undruggable,” due to its association with increased levels in the progression of Parkinson’s disease.
Neurodegenerative diseases, including Parkinson’s disease, present significant challenges in terms of therapy development. This is largely due to the difficulty in targeting specific proteins such as α-synuclein, which are known to be involved in disease progression.
Conventional methods for targeting proteins like α-synuclein, such as antibodies or antisense oligonucleotides, are limited in their efficacy when it comes to intrinsically disordered proteins. These proteins lack stable three-dimensional structures and typical small-molecule binding sites or pockets, which are typically targeted by traditional drug compounds.
By developing a method to target the mRNA structure responsible for encoding α-synuclein before it forms the protein, the researchers have created a tool that bypasses the challenge of directly targeting the fully formed protein. This method effectively limits the initial production of α-synuclein, offering a promising strategy for addressing its abnormal accumulation in Parkinson’s disease.
In experiments using neurons derived from Parkinson’s disease patients, the researchers found that Syn-RiboTAC indirectly restored the expression of approximately half of the dysregulated genes. The reduction in α-synuclein levels likely allowed for the restoration of genes that had been disrupted due to its abnormal accumulation. Furthermore, the decrease in α-synuclein may alleviate cellular stresses, enabling cells to regain normal function and gene expression patterns.
These findings represent a significant breakthrough, demonstrating that traditionally “undruggable” proteins like α-synuclein can be targeted through mRNA binding. This expands the druggability of disease-related proteins by utilizing small molecule binders and degraders.
Currently, there is no cure for Parkinson’s disease, and there is a crucial need for effective treatments that provide symptom relief and improve quality of life. This new strategy holds promise but requires further research in a clinical therapeutic setting. Addressing the expanded druggability of currently “undruggable” proteins could have a profound impact on the treatment of various diseases.
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1. Source: Coherent Market Insights, Public sources, Desk research
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