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The study, published in Nature Communications, found that loss of the RNA processing protein, SFPQ, in motor neurons results in their ‘dying back’. This involves destruction of the axon (the part of the neuron responsible for connecting to and communicating with the rest of the body) and later, cell body death.

Using zebrafish, the investigators explored what happens inside SFPQ-depleted motor neurons before they degenerate. They found that draft messenger-RNAs (mRNAs) that are normally regulated by SFPQ are only partially edited and become truncated. To their surprise, these defective mRNAs are not degraded but instead stably localise to axons, where they accumulate and interfere with normal function. This is the first study to show the cascade of molecular events in axons triggered by loss of the protein.

Finding the same mRNA abnormalities in zebrafish SFPQ mutant and in human ALS neurons is opening a new path in understanding the neurodegenerative process. 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.
Corinne Houart, Professor of Developmental Neurobiology at King’s IoPPN and the study’s lead author

The researchers will now turn their focus to determining the mechanisms by which these defective mRNAs are toxic in ALS patient axons, and will investigate the effect of introducing normal SFPQ into patient iPSC-derived degenerating neurons.

 

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Kings College

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www.kcl.ac.uk