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ALS-related mutations prevent RNA transport in nerves

Annexin A11, which has been linked to a rare form of ALS, may play a critical role in the transport of RNA granules throughout neurons. It hitches the granules onto lysosomes, which motor proteins carry along microtubules. NINDS

Amyotrophic lateral sclerosis (ALS) is a paralyzing and highly fatal neurodegenerative disorder. It affects the nerve cells that control voluntary movement. No cure has been found, but treatments can help control symptoms.

Genetic studies have found that ALS is often linked to mutations in genes related to RNA processing or lysosomes, the specialized compartments (or organelles) in cells that break down and get rid of cellular waste.

RNA carries the blueprints for making proteins. These instructions are first transcribed from DNA into RNA in the nucleus. Afterward, RNA is packaged into granules and transported out of the nucleus to other parts of the cell. RNA in nerve cells may have to travel great distances—sometimes up to four feet—down projections called axons to reach the other end of the cell. However, it’s been unclear how RNA gets carried around.

A team led by Drs. Michael Ward at NIH's National Institute of Neurological Disorders and Stroke (NINDS), Jennifer Lippincott-Schwartz at the Howard Hughes Medical Institute, and Peter St. George-Hyslop at the Cambridge Institute for Medical Research explored how RNA granules travel around nerve cells using advanced live cell microscopy. Their study was published online on September 19, 2019, in Cell.

The researchers first fluorescently labeled RNA granules and several different types of organelles. They found that moving RNA granules were usually associated with lysosomes, especially when they traveled down microtubules, which form the scaffolding that proteins travel around cells on.

The team was able to identify 130 proteins that interacted with the lysosomes. They then compared these proteins with a previously generated list of proteins linked to RNA granules. They found six proteins that interact with both RNA granules and lysosomes. The strongest was a protein that’s linked to ALS called annexin A11 (ANXA11).

The researchers discovered that ANXA11 interacted with both RNA granules and lysosomes in living cells. Mutations in ANXA11 that are associated with ALS disrupted these interactions. The team found that ANXA11 tethers RNA granules to lysosomes that are traveling along microtubules. Disease-causing mutations in ANXA11 prevented this “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,” Ward says. “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.”