How cells keep RNA from clumping under stress — and why it matters for neurodegenerative disease

A new study from the University of Michigan’s Stephanie Moon Lab offers fresh insights into how cells manage molecular crises.

Stephanie Moon, assistant professor of human genetics, has for years focused on how cells respond to stress, and the resulting RNA-protein clumps that are close relatives of the amyloid plaques found in many neurodegenerative diseases like amyotrophic lateral sclerosis, or ALS.

The fundamental insights gained from the new study could ultimately help inform the development of new treatments and therapeutic interventions to maintain healthy protein synthesis in diseases where the stress response goes awry.

That’s where fundamental science becomes human-centered.

“Discovering new therapeutics for neurodegeneration is critical,” Moon said, “But where do you start?”

Her answer: look upstream.

In healthy cells, most RNA molecules are covered with ribosomes, which function like miniature factories, translating genetic instructions in RNA into the proteins essential for cellular function.

When cells are stressed by heat, toxins, inflammation or other challenges, most cellular processes, including protein production, are temporarily shut down to help the cell survive.

Ribosomes typically detach or “run off” RNAs as part of this response. These unprotected RNAs then attract protein molecules like two polar-opposite magnets and clump together in blobs called “stress granules.” These “reversible” RNA-protein condensates act as temporary storage sites until conditions return to normal, and the stress granules typically “dissolve.”

Sometimes, stress granules can linger persistently and “harden” or aggregate from their normal liquid-like state to a gelatinous, solid consistency much more difficult to break down and clear — a road that could lead to pathogenesis.

Understanding the integrated stress response pathway is therefore paramount to Moon and her team, since neurodegenerative diseases like ALS, Alzheimer’s and frontotemporal dementia have long been linked to RNA-protein aggregates, making them close cousins of the stress granules Moon and her team are studying.

To avert the pathogenic highway and help the cell recover and adapt, Moon and her team knew that certain mRNAs (messenger RNAs) needed to be expressed during stress.

“These specialized mRNAs are like emergency vehicles speeding toward a wreck on an interstate highway where they can quickly respond,” Moon said. “Some of the ‘regular’ traffic (other mRNAs) is sent off the road (into granules) during the crisis.”

Before this study, it wasn’t clear if or how these specialized mRNAs were kept out of stress granules. While many studies hinted that translation of these mRNAs during stress would exclude them from stress granules, other recent studies found evidence that these mRNAs could translate inside stress granules.

This study, published in the journal Genes & Development and first-authored by Ph.D. candidate Noah Helton, showed that these vital mRNAs escape stress granules by interacting with ribosomes. Trapping these mRNAs in stress granules would halt their protein production at a time when the cell may need them most.

In their experiments, they confirmed that “extra instructions” tacked onto these mRNAs led to greater association with ribosomes under stress. Removal of those instructions caused loss of ribosome association, and more of the mRNAs ended up in stress granules. They also found that having just one ribosome attached to mRNA is enough to keep them out of stress granules, flipping an established “multiple ribosomes” theory on its head.