ALS gene linked to lysosomal transport of RNA in neurons

Affecting at least 14,000 Americans, amyotrophic lateral sclerosis (ALS) is a paralyzing and highly fatal neurodegenerative disorder for which there are no effective treatments.

Scientists peered inside neurons and watched the workings of annexin A11, a gene linked to a rare form of ALS. They found that neurons may normally use the gene to ship internal housekeeping instructions via a newly discovered "hitchhiking" system and that disease-causing mutations may tie up deliveries at the cell's loading docks. The study was published in the journal Cell.

Neurons, like other cells, constantly manufacture proteins, the cell's workhorses. Instructions for making proteins are encoded in chromosomal DNA and stored in the nucleus. Manufacturing starts when DNA instructions are transcribed into RNAs, which are packaged as granules and transported out of the nucleus to other parts of the cell for assembly. Unlike in other cells, RNA in neurons may have to travel over great distances - sometimes up to four feet - down stringy axons or through dendritic branches.

Using advanced live cell microscopy, the researchers found that annexin A11 plays a role in this process by helping RNA granules hitch rides onto traveling lysosomes. Until recently, lysosomes were mainly viewed as garbage cans that roam around inside of cells cleaning up waste. ANXA11 possesses an N-terminal low complexity domain, facilitating its phase separation into membraneless RNA granules, and a C-terminal membrane binding domain, enabling interactions with lysosomes. These unexpected results suggest that lysosomes might moonlight as RNA transporters.

They also found that disease-causing mutations in annexin A11 prevented hitchhiking, which, in turn, prevented RNA from being delivered to the far reaches of neurons. Many genetic studies have found that ALS is often caused by mutations in genes known to play roles in either RNA processing or the control of lysosomes. These results suggest that there is a link between these seemingly different processes and that understanding this type of hitchhiking in neurons may lead to new treatments for ALS.

https://www.ninds.nih.gov/News-Events/News-and-Press-Releases/Press-Releases/ALS-gene-may-be-hitchhiker’s-guide-neuron

https://www.cell.com/cell/fulltext/S0092-8674(19)30969-9