A new sign of amyotrophic lateral sclerosis (ALS) reveals possible triggers for neurodegeneration

A new study from the Institute of Psychiatry, Psychology and Neuroscience (IoPPN) at King's College London has identified a new hallmark of the neurodegenerative disease amyotrophic lateral sclerosis (ALS), revealing possible molecular triggers
for the disease.

The study, published in the journal Nature Communications, found that the loss of the RNA-processing protein SFPQ in motor neurons causes their "death.
"
This involves the destruction of axons (the parts of neurons responsible for connecting and communicating with the rest of the body), and the subsequent death
of the cell body.

Using zebrafish, the researchers explored what happens
to motor neurons missing SFPQ before they degenerate.
They found that draft messenger RNAs (mRNAs), which are normally regulated by SFPQ, are only partially edited and truncated
.
To their surprise, these defective mRNAs were not degraded, but instead stably localized on axons, where they accumulated and interfered with normal function
.
This is the first study to show the cascade
of axonal molecular events due to protein loss.

Since the loss of SFPQ is strongly associated with ALS, the authors extracted their findings from zebrafish and analyzed data
from ALS patients.
They found that unusual defective mRNAs were enriched in the patient's neurons, pointing to these axonal mRNAs as the cause of
disease degeneration.

Corinne Houart, Professor of Developmental Neurobiology at King's College and lead author of the study, said: "Finding the same mRNA abnormalities in zebrafish SFPQ mutants and human ALS neurons opens up a new avenue
for understanding neurodegenerative processes.
Our findings, as well as those of our international colleagues, suggest that controlling axonal mRNA diversity is critical
for neurological health.
Finding local changes in neuronal mRNA regulation affected by aging or neurological disorders will provide tremendous progress
in addressing these issues.
”

It is estimated that around 5000 people in the UK at any one time have amyotrophic lateral sclerosis
.
The average survival time after diagnosis is between 2 and 5 years, and there is currently no effective treatment
.
This discovery opens up a possible new avenue for the treatment of ALS patients, aiming to restore SFPQ function
in neurons.
By doing so, they can be prevented from degrading
.

Dr Richard Taylor, first author of the study, said: "We were surprised to find that these abnormal mRNAs, formed due to loss of SFPQ function, were not degraded
in the nucleus.
On the contrary, contrary to dogma, they seem to escape and are specifically localized to axons
.
Their effects at the RNA level or protein level, if translated, can be detrimental to axon integrity and may initiate the 'death regression' sequence
of degenerative degeneration observed in ALSCLEROSIS neurons.
”

The researchers will now turn their attention to determining the mechanism of toxicity of these defective mRNAs in axons in ALS patients, and will investigate the effect of
introducing normal SFPQ into patients' iPSC-derived degenerate neurons.