Scientists have explained why a common genetic variant worsens disease outcomes for people with adult-onset neurodegenerative diseases, it has been announced.
A study, by UCL, London, UK, and US-based National Institutes of Health (NIH), reveals that TDP-43 protein depletion, which is associated with 97% of amyotrophic lateral sclerosis (ALS) cases and half of frontotemporal dementia (FTD) cases, corrupts the genetic instructions for the critical neuronal protein UNC13A.
Writing in the latest edition of *Nature*, the researchers say a mysterious genetic variant previously associated with disease risk increases the chance of UNC13A’s genetic instructions being corrupted among people with the diseases.
This worsens the risk and severity of ALS and FTD.
UNC13A enables neurons to communicate with each other via neurotransmitter release, and it is believed its loss from neurons can be fatal.
The researchers believe the corruption of UNC13A’s genetic instructions may have similar consequences, adding their discovery raises hope for new treatments.
Co-corresponding author Dr Michael Ward, of the National Institute of Neurological Disorders and Stroke, NIH, said: “We have known for a long time that genetic variants in UNC13A cause an increased risk of ALS and dementia, but nobody had figured out why this is the case.
“Together, our teams showed exactly how this genetic risk factor for ALS interplays with the core disease mechanism, TDP-43 loss, in order to worsen the disease course.”
As part of the experimental study, the researchers used skin-derived human stem cells to make neuronal cells in dishes and removed the TDP-43 protein from these cells using a new technology based on CRISPR-Cas9.
They studied how these neurons without TDP-43 differed from healthy neurons and found that the mRNAs for the UNC13A protein were corrupted, which resulted in the ribosomes in the lab-grown neurons being unable to correctly produce the UNC13A protein.
When they looked at ALS and FTD patient brain samples, they found that the mRNAs for UNC13A were incorrect.
They say that given the essential role UNC13A plays in facilitating neuron communication, its corruption is likely to impair neuronal function and contribute to neurodegeneration in those with ALS and FTD.
Corresponding author Professor Pietro Fratta, of UCL Queen Square Institute of Neurology, said: “We have built on years of genetic research that identified that UNC13A was implicated in motor neuron disease and FTD, and supported it with a new molecular biology finding that confirms that the gene is absolutely fundamental to the disease process.
“We are hoping to carry out trials over the coming years to develop such a treatment that could potentially greatly improve the lives of people living with ALS.”
Brown AL, Wilkins OG, Keuss MJ et al. TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A. *Nature* 23 February 2022; doi: 10.1038/s41586-022-04436-3
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