RNA Aptamer Emerged as Potential Strategy for Synucleinopathies

Synucleinopathies are a group of neurodegenerative disorders that includes serious conditions such as Parkinson's disease and dementia with Lewy bodies. There are currently no cures for these disorders and treatment is limited to mitigating symptoms. Recently, antibody-based therapies have attracted considerable attention, but alternative approaches are still necessary.

Therapy development for synucleinopathies tends to target the alpha-synuclein protein, αSyn, the abnormal aggregation of which is a hallmark of these diseases. However, targeting this protein using conventional strategies for drug discovery is stymied by the molecule's lack of a stable three-dimensional structure, which cultivates aggregation.

Interested in understanding how abnormal protein aggregation drives neurodegeneration, a team of researchers at Kyoto University had an idea that was both scientifically intriguing and therapeutically promising: could RNA aptamers -- often described as "chemical antibodies" - directly recognize αSyn's disordered regions and suppress pathological aggregation?

To explore this possibility, the researchers first performed in vitro selection against the αSyn1-95 region, which contains lysine-rich repeat sequences that facilitate aggregation. After screening a mind-numbing number of RNA candidates, the team was able to identify the RNA aptamer 1R6, which has a high affinity for αSyn.

"Screening 10¹⁴ RNA candidates felt a bit like playing a giant gacha machine," says corresponding author Kazuma Murakami. "Discovering 1R6 was our 'gotcha' moment."

Following this discovery, the scientists evaluated the aggregation, oligomerization, fibril formation, and disaggregation of αSyn with biochemical assays and electron microscopy. They then used cellular and Drosophila models of synucleinopathy to assess the therapeutic effects of 1R6, and used NMR spectroscopy and computational modeling to investigate its binding mechanism to αSyn.

The results revealed that the 1R6 RNA aptamer inhibited both αSyn aggregation and fibril formation, and even promoted the disassembly of pre-existing aggregates. The researchers also observed beneficial effects in the cellular and Drosophila models that exceeded their initial expectations.

"Intrinsically disordered proteins such as αSyn have long been considered difficult targets for drug discovery," says Murakami. "We've now demonstrated that an RNA aptamer can recognize these flexible regions and even promote the disassembly of pathogenic aggregates."

This study provides a new therapeutic strategy for neurodegenerative disorders and opens the door to targeting other aggregation-prone proteins. The team hopes their finding will contribute to the development of new therapies for synucleinopathies and broaden the scope of aggregation-targeted drug discovery. Next, they plan to improve the expression and delivery of RNA aptamers while evaluating their efficacy and safety in a broader range of mammalian disease models.