RNA-targeting Molecule May Open New Avenue For Treating Parkinson’s, Study Suggests

A new small molecule called synucleozid can prevent cells from producing the Parkinson’s-associated protein alpha-synuclein by inhibiting its translation from RNA, a study shows.

The study, “Translation of the intrinsically disordered protein α-synuclein is inhibited by a small molecule targeting its structured mRNA,” was published in the journal Proceedings of the National Academy of Sciences. It supports the strategy of targeting RNA as a way of treating disorders that involve proteins that are resistant to drug-based manipulation.

Most therapies work by binding to protein targets within the body, and their design has been focused on developing small molecules that can affect proteins. However, more than 80% of the proteins made in the human body can’t be pharmacologically targeted.

Such is the case with alpha-synuclein, a protein known to form clumps (Lewy bodies) in the brains of people with Parkinson’s disease, which can be toxic to brain cells.

Lessening the amount of alpha-synuclein in the brain is a goal for many developers of Parkinson’s therapies. However, targeting the protein itself isn’t feasible because alpha-synuclein’s structure tends to shift, making it hard to design molecules that can consistently bind to it. It’s considered an intrinsically disordered protein.

Proteins are made by cellular machinery that transcribes genes encoded in DNA into RNA, which is then translated into the protein itself. The researchers set out to find a small molecule that could reduce alpha-synuclein by targeting the RNA instead of the protein.

Several investigational compounds currently being tested for Parkinson’s are antibodies that target a late stage of alpha-synuclein protein aggregates. A team at Rutgers University in New Jersey and the Scripps Research Institute in San Diego wanted to see if they could prevent these protein clumps from forming in the first place.

They targeted a feature of the RNA that encodes alpha-synuclein: an iron-responsive element (IRE) that limits translation of the RNA into alpha-synuclein protein when iron concentrations are too low.

Using a computer program called Inforna, they designed small molecules to specifically bind to the IRE —essentially, mimicking the translation-inhibiting effects, but in a way that was independent of iron concentration.

The lead compounds were synthesized and tested on cells in dishes. A compound the researchers named synucleozid was found to be the most effective.

At a concentration of 1 micrometer, it inhibited about 40% of alpha-synuclein translation. It also lowered cell death in a dose-dependent manner when cells were co-cultured with synucleozid and with toxic alpha-synuclein clumps. There was no evidence to indicate that synucleozid treatment itself caused any damage to the cells.

Molecular analysis showed that synucleozid was acting as anticipated, physically binding to alpha-synuclein-encoding RNA at the IRE region and preventing translation.

The small molecule was also screened for any unintended effects on other RNA or proteins in the brain.

Synucleozid showed high selectivity for alpha-synuclein.

The technique affected other proteins, such as ferritin, which regulates iron, but to a lesser extent than alpha-synuclein. For instance, cells’ production of ferritin was decreased by about 10% after treatment with 1 micrometer of synucleozid. The same effect on alpha-synuclein was achieved with a concentration four times lower.

“[T]hese findings provide a promising approach for achieving disease modification in alpha-synuclein associated neurodegenerative disorders, including Parkinson’s disease and dementia with Lewy bodies,” the researchers said.

More research will be needed to see whether the technique can be safely and effectively translated into treating humans. Modifications will likely be necessary to make the molecule able to get into the brain, the researchers said.  

The study bolsters the case for targeting structural elements in RNA as a way of treating difficult-to-drug proteins. For example, similar regulatory sequences have been identified in the RNA that codes for the protein huntingtin, abnormal forms of which cause Huntington’s disease.

“We are just at the beginning here, and there is much work to do,” Matthew D. Disney, PhD, a chemistry professor at Scripps Research and an author of the study, said in a press release. “We are showing that if you can inhibit a protein from being made, that may be advantageous over waiting to address its role in disease until after it is already made.”