α-synuclein regulates neurotransmitter release, supports learning and memory, and maintains neuronal health (1). However, overproduction due to genetic factors like duplication of the α-synuclein gene can predispose it to aggregate, causing neuronal damage, synaptic dysfunction, and ultimately Parkinson’s disease. A promising preventative strategy is reducing α-synuclein levels. 

“For a lot of these diseases that are caused by aggregation-prone proteins, there could be significant advantage to targeting the intracellular form before it aggregates,” said Matthew Disney, a biophysical chemist at The Wertheim UF Scripps Institute. As mRNA are translated multiple times to form proteins, degrading the mRNA could circumvent the problem of protein aggregation by reducing protein levels.

In a new study, Disney’s team and his collaborators at Rutgers Robert Wood Johnson Medical School Institute for Neurological Therapeutics reported on the development of a chimeric small molecule that selectively binds to and inhibits the translation of α-synuclein mRNA, reducing its protein levels in cultured neurons (2). The findings, published in Proceedings of the National Academy of Sciences, offer a new therapeutic strategy for diseases like Parkinson’s disease, where the target protein is otherwise considered undruggable due to a disordered structure lacking the typical small molecule binding pockets.

“The big strength of this study is the idea of having a small molecule that can target gene expression quite specifically and quite cleanly,” said Anurag Tandon, a neuropharmacologist at the University of Toronto who was not involved in the study.

Through a screening process, the researchers first discovered an RNA-binding small molecule that prevents ribosomes from assembling onto α-synuclein mRNA, decreasing the production of α-synuclein. They then converted it into a ribonuclease-targeting chimera called Syn-RiboTAC, which binds α-synuclein mRNA and recruits an RNA-degrading enzyme. This leads to the targeted destruction of α-synuclein mRNA in cells, reducing α-synuclein levels. 

Syn-RiboTAC reduced α-synuclein levels in dopaminergic neurons derived from the induced pluripotent stem cells (iPSC) of a patient with Parkinson’s disease, aligning α-synuclein levels with those in healthy neurons.

For a lot of these diseases that are caused by aggregation-prone proteins, there could be significant advantage to targeting the intracellular form before it aggregates, 
- Matthew Disney, The Wertheim UF Scripps Institute

RNA sequencing and proteomics studies showed that Syn-RiboTAC selectively rescued about 50 percent of the genes abnormally expressed in dopaminergic neurons derived from the iPSC of patients with Parkinson’s disease. For instance, levels of hexokinase 2, a gene implicated in the apoptosis of dopaminergic neurons, dropped significantly after Syn-RiboTAC treatment.

“It’s becoming apparent for all these diseases like Parkinson’s that you really need whole-body suppression of the RNA of the toxic protein to have a therapeutic application,” said Disney. However, while there is a theoretical basis to expect protection against pathology due to reduced intracellular expression, this aspect has not yet been tested in vivo. 

“We won’t know whether this works until it goes to an animal model,” said Tandon. Key questions that remain include whether the treatment is effective when delivered directly to the brain, or if peripheral delivery reaches the brain and yields positive outcomes. 

Disney’s team is also working on a similar mRNA targeting strategy to degrade tau, another aggregate-prone protein implicated in Alzheimer’s disease. “[This mRNA-targeting strategy] has broad utility,” said Disney. “It's just another tool in your toolbox to go after some of these targets.”

References

1. Saleh, H. et al. Mini review: linkage between α-Synuclein protein and cognition. Transl Neurodegener  4, 5 (2015).
2. Tong, Y. et al. Decreasing the intrinsically disordered protein α-synuclein levels by targeting its structured mRNA with a ribonuclease-targeting chimera. Proc Natl Acad Sci  121, e2306682120 (2024).