Defining conserved functions of RNA binding proteins in stress-granule biogenesis

RNA is a mobile form of genetic information that is made from our DNA and its complex regulation is extremely important to the proper functioning of our cells. Since the discovery of TDP-43 in 2006 as a substance that plays a major role in ALS, the hypothesis that abnormal regulation of RNA is critical to the disease has come to the forefront. In the past decade, this has only strengthened as numerous newly-identified ALS genes pointed to an influence on RNA biology.

One of the standard features of RNA biology is the formation and disintegration of structures called stress granules that are created temporarily to protect RNA and RNA-binding proteins in times of potentially harmful environmental triggers. However, in ALS it has been observed that stress granules fail to properly break apart. In this Discovery Grant, Dr. Eric Lécuyer will use an unprecedented library of tools that recognize RNA binding proteins in stress granules to better understand their content in human stem cells derived from people living with ALS. Furthermore, Dr. Lécuyer will use a second set of tools developed in his lab to systematically remove RNA binding proteins from stress granules to determine which ones are critical to the proper formation and disintegration, and finally, determine how they play a role in toxicity to motor neurons in ALS.

An earlier Discovery Grant and Hudson Grant team have focused on understanding the content and dynamics of stress granules in ALS using other methods and the work of Dr. Lécuyer should complement these efforts well in a way that brings strong expertise into an already world-leading team effort in Canada. The magnitude of evidence that abnormal RNA biology is a key factor in how ALS is caused has grown considerably in recent years and finding ways to normalize areas of malfunction may represent one of the best avenues for discovering treatments that are significantly effective in slowing down the disease.