New Hallmark of Motor Degeneration in ALS Identified

Loss of the RNA processing protein, SFPQ, in motor neurons has been identified as a probable molecular mechanism underlying the progression of amyotrophic lateral sclerosis (ALS) and a significant hallmark of the disease. These new findings, published in Nature Communications, come from a research team at the Institute of Psychiatry, Psychology & Neuroscience (IoPPN) at King’s College, London.

"We were surprised to find that these abnormal mRNAs, forming upon loss of SFPQ function, are not degraded in the nucleus,” said first author Richard Taylor, PhD, IoPPN, King’s College, London. “Instead, contrary to dogma they seem to escape and specifically localize to axons.” Their effects either at the RNA level, or protein level if translated, are likely detrimental to axon integrity and may initiate the 'dying back' sequence of degeneration observed in ALS neurons."

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The study authors first used zebrafish to examine what happens inside of motor neurons that are low on SFPQ. Draft messenger-RNAs (mRNAs) are only partially edited due to the lack of processing protein, but still are shuttled to axons. The defective mRNAs interfere with regular functioning as they accumulate in the axon.

Previous studies have established a strong association between loss of SFPQ. Thus, the researchers utilized their zebrafish findings in comparison to data from human ALS patients. They found the same mRNA defects in ALS patient neurons, indicating that the accumulation of defective mRNA in axons in humans may also be a cause for degeneration over the course of the disease.

“Finding the same mRNA abnormalities in zebrafish SFPQ mutant and in human ALS neurons is opening a new path in understanding the neurodegenerative process,” wrote lead author Crinne Houart, professor of developmental neurobiology at IoPPN, King’s College, London. “Our findings as well as those of international colleagues show that controlling mRNA diversity in axons is essential of neuronal health. Uncovering the local changes in mRNA regulation in neurons affected by aging or neurological disorders will provide great progress in tackling these issues."

References

Researchers reveal a new ALS hallmark, shedding light on a likely trigger of neurodegeneration. News Release. King’s College London. November 22, 2022. Accessed February 2, 2022.

Taylor R, Hamid F, Fielding T, et al. Prematurely terminated intron-retaining mRNAs invade axons in SFPQ null-driven neurodegeneration and are a hallmark of ALS. Nat Commun. 2022;13(6994). doi:10.1038/s41467-022-34331-4