The reduction of α-synuclein, which is central to the pathogenesis of Parkinson’s disease and other α-synucleinopathies, can be accomplished through the binding and selective degradation of its corresponding mRNA. Since α-synuclein is an intrinsically disordered protein, it is frequently referred to as “undruggable” because it lacks pockets that small molecules can bind to.
Researchers from the lab of Matthew Disney, PhD, at the Scripps Research Institute campus in Florida, converted the RNA-binding small molecule into a ribonuclease-targeting chimera (RiboTAC), significantly enhancing its potency while retaining selectivity on the transcriptome and proteome. This study gives credence to the assertion that small molecules can target human RNA structural elements and impart riboswitch-like control to translation by using exogenously delivered small molecules.
The article, “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).
Attacking Parkinson’s with RiboTACs
In Parkinson’s disease and other α-synucleinopathies, α-synuclein misfolds, oligomerizes, and forms fibrils that spread across neurons, gather in Lewy bodies and Lewy neurites, and propagate neural degeneration. A major factor that promotes α-synuclein fibrillization is its concentration, as individuals with multiplication of the SNCA gene locus develop dominantly inherited Parkinson’s disease with a gene dosage effect.
Co-lead authors Yuquan Tonga and Peiyuan Zhang examined a group of RNA-focused compounds similar to drugs to see how they would bind to the 5′ UTR of SNCA mRNA. This approach yielded Synucleozid-2.0, a drug-like small molecule that decreases α-synuclein levels by inhibiting ribosomes from assembling onto SNCA mRNA.
This RNA-binding small molecule was converted into a RiboTAC to degrade cellular SNCA mRNA. RNA-seq and proteomics studies demonstrated that the RiboTAC selectively degraded SNCA mRNA to reduce its protein levels affording a five-fold improvement in cytoprotective effects than Synucleozid-2.0.
In addition to the pathogenesis caused by α-synuclein, transcriptome-wide changes in RNA expression are observed in Parkinson’s. Syn-RiboTAC also rescued the expression of ~50% of genes that were abnormally expressed in dopaminergic neurons differentiated from Parkinson’s disease patient-derived induced pluripotent stem cells (iPSCs).
The case for RiboTACs
Crucially, unlike small molecules with binding mechanisms of action, RiboTACs do not need to bind to functional sites to produce activity. Instead, they can bind to biologically inert sites and cause endogenous nucleases to degrade them.
Furthermore, it is well known that oligonucleotide modalities—many of which have received FDA approval—are the most widely used means of eliciting functional effects to eradicate disease-causing RNAs. These large molecular-weight compounds, however, are typically injected medications with poor brain penetrance and limited tissue distribution.
Targeted RNA degradation using heterobifunctional molecules such as RiboTACs could be further advanced to provide molecules with broader tissue distribution that could also be developed into orally bioactive medicines.