Targeting the mRNA of “undruggable” proteins in the fight against Parkinson’s disease

Researchers at the Scripps Research Institute in Florida have developed a new method to counteract levels of α-synuclein protein by targeting the mRNA that forms them. The strategy opens many doors for research with potential therapeutic approaches to combat neurodegenerative diseases.

In an article titled “Decreasing intrinsically disordered α-synuclein protein levels by targeting its structured mRNA with a ribonuclease-targeting chimera,” published in PNASthe team presents Synucleozid-2.0 and Syn-RiboTAC, an mRNA binding and degradation duo that enabled the modulation of the highly undruggable protein, α-synuclein, by targeting its encoding mRNA.

Neurodegenerative diseases, particularly Parkinson’s disease (PD), pose significant therapeutic challenges due to the difficulty in targeting specific proteins such as α-synuclein, whose levels increase associated with disease progression.

Conventional methods, such as antibodies or antisense oligonucleotides, are limited when targeting intrinsically disordered proteins such as α-synuclein because they lack stable three-dimensional structures, binding sites, or pockets. typical of small molecules, which are often the conventional targets of drug compounds.

By creating a method to target the coding structure of the mRNA before it forms the protein, the researchers have created a tool that can circumvent the difficulty of targeting the fully formed protein by limiting its initial production levels.

In neurons derived from PD patients, Syn-RiboTAC indirectly restored the expression of approximately half of the dysregulated genes. The reduction in α-synuclein levels likely allowed the restoration of some dysregulated genes disrupted by its abnormal accumulation. The downstream effects of α-synuclein reduction could also alleviate cellular stress, allowing cells to return to normal function and gene expression patterns.

The results represent a major advance, illustrating that traditionally “druggable” proteins like α-synuclein can be targeted via mRNA binding, thereby increasing the druggability of disease-related proteins through small molecule binders and degrading.

As Parkinson’s disease is currently incurable, effective treatments to relieve symptoms are necessary to maintain quality of life. The new strategy requires further research in a clinical therapeutic setting where many unmet medical needs urgently await increased druggability of currently undruggable proteins.

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