Parkinson’s disease is a debilitating condition that can be caused by elevated levels of the intrinsically disordered protein α-synuclein, which lacks typical small-molecule binding pockets. However, a recent research article published in the field of applied biological sciences presents a promising approach to combat this issue.
The study, led by Yuquan Tong, Peiyuan Zhang, Xueyi Yang, and Matthew D. Disney, focuses on targeting the structured mRNA of α-synuclein to decrease protein levels in patient-derived neurons. This innovative approach aims to redefine the druggability of so-called ‘undruggable’ proteins by leveraging small molecules that bind to the encoding mRNA.
One of the key findings of the research is the development of Synucleozid-2.0, a drug-like small molecule that effectively reduces α-synuclein levels by inhibiting ribosomes from assembling onto SNCA mRNA. This represents a significant advancement in the quest to address the challenges posed by intrinsically disordered proteins.
Moreover, the study goes beyond mere inhibition by introducing a ribonuclease-targeting chimera (RiboTAC), which further enhances the potency of the RNA-binding small molecule. The resulting Syn-RiboTAC demonstrated selective degradation of SNCA mRNA, leading to a fivefold enhancement of cytoprotective effects compared to Synucleozid-2.0.
Importantly, the implications of this research extend beyond the specific case of α-synuclein and Parkinson’s disease. The platform developed by the researchers has the potential to expand the druggability of challenging disease targets by targeting the encoding mRNA with small molecules.
Furthermore, the study conducted RNA-seq and proteomics studies, which revealed that Syn-RiboTAC not only reduced α-synuclein protein levels but also rescued the expression of approximately 50% of genes that were abnormally expressed in dopaminergic neurons derived from Parkinson’s disease patient–derived iPSCs. This underscores the broad impact and potential therapeutic relevance of the research findings.
