Can new understandings about RNA granules explain types of ALS?

Over the past several years, ALS researchers have learned that little structures in motor neurons called RNA granules are one of the most common biological differences in people with ALS and frontotemporal dementia compared to people without those diseases.

These small ball-like granules are made of RNA, molecules that relay the genetic instructions in DNA, as well as specialized proteins that bind to RNA to influence its activity. Such granules form when motor neurons are exposed to potentially harmful factors, or as a result of ALS-associated mutations that affect specific RNA molecules or RNA binding proteins.

The formation of RNA granules is normally a fluid process required to help cells adapt to their environment. But in ALS, the formation and breakdown of RNA granules appear to be abnormal. “These RNA granules are thought to act like sponges that sequester away important cellular components and prevent them from doing their normal functions,” said Dr. Eric Lécuyer, a researcher at l’Institut de recherches cliniques de Montréal. He was awarded an ALS Canada-Brain Canada Discovery Grant in 2016 to study RNA granules and RNA binding proteins related to the familial forms of ALS.

With a project grant of $125,000 from the ALS Canada Research Program in 2018, Dr. Lécuyer will continue to advance international ALS research by exploring and describing RNA granules in greater detail. “The research focus on RNA is really booming. Disrupted RNA processes are emerging as key players in many diseases, especially neurological and neuromuscular disorders,” said Dr. Lécuyer.

Earlier discoveries

In his earlier research, Dr. Lécuyer discovered that a specific class of RNA granules, called stress granules, were more numerous, larger and more persistent in cells derived from people with ALS compared to people without ALS. He used an extensive library of more than 300 antibodies to identify RNA binding proteins in stress granules with advanced imaging techniques. This work was part of a productive collaboration with Dr. Gene Yeo, an RNA researcher at the University of California San Diego.

Advancing ALS research

For his current project, Dr. Lécuyer will study RNA granule formation caused by abnormalities in the C9orf72 gene, the most frequent genetic cause of ALS and frontotemporal dementia.

Additionally, as a member of an international consortium of RNA researchers who are collaborating to understand how RNA binding proteins are involved in many disease processes, Dr. Lécuyer’s laboratory has created a large, international open database called the RBP Image Database (RNA Binding Protein Image Database). Through his work, he will create a similar database containing >100,000 images of RNA and RNA binding proteins associated with the formation of RNA granules in C9orf72-ALS or other ALS subtypes. This “ALS RBP Image Database” is a unique and valuable resource that ALS researchers around the world can access for free.

If he identifies specific RNA binding proteins associated with the formation of abnormal RNA granules in ALS, Dr. Lécuyer will explore how granule formation is associated with neurodegeneration in ALS by conducting experiments in human cellular models and with fruit flies that have been genetically modified to mimic human ALS.

Ultimately, Dr. Lécuyer hopes to find similarities in the RNA granules observed in different subtypes of ALS. “If we can identify similar defects in RNA granules that link various subtypes of ALS, that may explain a common molecular cause of the disease that could set the stage for future research and, ultimately, guide the development of new therapeutic strategies,” Dr. Lécuyer said.

This research project is one of 8 research projects funded in 2018 by the ALS Canada Research Program, which is the only dedicated source of funding for ALS research in Canada. The funding of the project followed a rigorous scientific assessment by panels of global ALS experts. The panellists evaluated a larger pool of applications to identify the projects that demonstrate scientific excellence and have the potential to most quickly advance the field of ALS research in order to develop effective treatments.