Researchers Shed Light on Link Between Nuclear Protein and MS

A nuclear protein called heterogeneous nuclear ribonucleoprotein A1 or hnRNP A1 — abnormally found outside the nucleus in people with neurodegenerative diseases such as multiple sclerosis (MS) — is essential for nerve cell function and survival.

Those are the findings of a new study, by Canadian researchers, of nerve cells grown in the lab. Combined with previous data showing that hnRNP A1 mislocalization is associated with the formation of toxic, persistent stress granules, these findings suggest that a combination of both the loss of hnRNP A1’s activity in the nucleus and its toxic effects outside of it likely result in neurodegeneration, the researchers said.

“A1 dysfunction in nerve cells causes nerve cell death and damage, also known as ‘neurodegeneration’ in MS patients,” Michael Levin, MD, the study’s senior author and a professor at the University of Saskatchewan (USask) College of Medicine, said in a university press release.

“We are hopeful that this [research] will lead to the discovery of medications that can be used in humans, which will inhibit neurodegeneration and improve the lives of persons living with MS,” said Levin, also chair of the Saskatchewan Multiple Sclerosis Clinical Research.

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The study, “Knock-Down of Heterogeneous Nuclear Ribonucleoprotein A1 Results in Neurite Damage, Altered Stress Granule Biology and Cellular Toxicity in Differentiated Neuronal Cells,” was published in the journal eNeuro.

The cell’s nucleus — which coordinates the cell’s activities — contains all of its genetic information and is where this information is transformed into messenger RNA (mRNA), an intermediate molecule that guides protein production. hnRNP A1 is a nuclear protein involved in mRNA production, modification, and transport.

Mislocalization of RNA-binding nuclear proteins, including hnRNP A1, in the cytoplasm — the cellular space that surrounds the nucleus — has been linked to neurodegenerative diseases such as amyotrophic lateral sclerosis, known as ALS, and MS.

This link has been hypothesized to be related to hnRNP A1’s loss of function in the nucleus and/or its gain of toxicity when in the cytoplasm — namely, in the form of abnormal, persistent stress granules. Stress granules are small clumps of RNA-bindings proteins and mRNA molecules that are naturally formed in response to cellular stresses.

While these clumps are typically disassembled once the initiating stress is relieved, in several neurodegenerative diseases they are abnormally sustained, and have been associated with the toxic buildup of other proteins.

Notably, Levin and his team previously found abnormal hnRNP A1-related stress granules in the brains of MS patients.

However, the effects of hnRNP A1’s nuclear loss in neurodegeneration remain poorly understood.

To address this, the team now analyzed gene activity, nerve cell health and function, and stress granule formation in lab-grown nerve cells with and without this nuclear protein.

First, the researchers found that 1,561 genes were differentially activated between these cells: 782 were significantly suppressed and 779 were significantly activated in neurons lacking hnRNP A1. These genes were mostly involved in biological processes related to RNA metabolism, assembly of RNA-binding protein complexes, and nerve cell function, structure, and death.

Notably, 89.9% of these genes provided instructions for making proteins known to bind hnRNP A1, “suggesting that perturbations in the identified [genes] might be due to lack of binding and proper processing” of the resulting mRNA molecules by hnRNP A1, the researchers wrote.

Further analyses confirmed that the loss of hnRNP A1 negatively affected the function and survival of nerve cells, as well as the assembly of stress granules.

In particular, nerve cells lacking hnRNP A1 showed significantly fewer and shorter structures involved in nerve cell communication, increased death, and significantly fewer and smaller stress granules relative to unaltered nerve cells.

These findings “confirm the vital role that hnRNP A1 plays in RNA metabolism and suggests that hnRNP A1 loss-of-function leads to impaired neuronal viability by induction of cell death pathways and dysregulated RNA processing,” the team wrote.

As such, the data support hnRNP A1 impairment as an important contributor to neurodegenerative diseases.

In addition, the team noted that while this study shed light on the mechanisms behind hnRNP A1 loss-of-function in the nucleus and neurodegeneration, a mechanistic link between cytoplasmic hnRNP A1 and neurodegeneration is still lacking.

“However, it is most likely a combination of both cytoplasmic gain of toxicity and nuclear loss-of-function of hnRNP A1 that results in neurodegeneration in neurologic diseases,” the researchers concluded.

The team is now using this information to test medications that reverse neurodegeneration in lab-grown nerve cells that mimic those found in people with MS.

“These findings have implications for a wide array of neurologic diseases,” the researchers said.

“Our goal is to prevent neurodegeneration, and in doing so, improve the lives of persons living with MS,” Levin added.