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Both adult-onset neurodegenerative amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are worsened by genetic variants in a single gene, and the reason for that may be clearer thanks to a recent scientific study.

The study shows how TDP-43 protein depletion, associated with almost all cases (97%) of ALS and half of FTD cases, disrupts genetic instructions for the neuronal protein UNC13A.  TDP-43 is an RNA-binding protein that resides primarily in the nucleus and has key regulatory roles in RNA metabolism, including as a splicing repressor.

The team also found that two genetic variants in UNC13A, which has been previously associated with these conditions, increase the chance of risk and severity of ALS or FTD. These polymorphisms overlap with TDP-43 binding sites.

This research was led by scientists at University College of London (UCL) and the National Institutes of Health (NIH), it was published in Nature this week.

Co-corresponding author Michael Ward, of the NIH’s National Institute of Neurological Disorders and Stroke, 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.”

UNC13A enables neurons to communicate with each other via neurotransmitter release, and data from animal models suggests its loss from neurons can be fatal. The researchers believe that mutations in UNC13A may have similarly harmful consequences.

ALS is the most common motor neuron disease and there is no known cure. FTD symptoms include language impairment, changes in personality, and cognitive difficulties. It is also currently incurable.

Researchers say the discovery raises hope for new treatments. Possibly by developing a therapy that blocks UNC13A mutations.

Corresponding author Professor Pietro Fratta, of the UCL Queen Square Institute of Neurology, said, “The majority of research into gene therapy has focused on genes implicated in familial ALS [patients with a family history of the disease], but the vast majority of ALS cases are sporadic, with no known family history.”

The UNC13A gene and its corresponding protein are of longstanding interest to motor neuron disease and FTD researchers, with previous studies showing common genetic variants increase the risk and severity of both the diseases. However, these variants are benign in most people unaffected by the diseases and half the population carries one of them. Despite over a decade of research, the exact reason for this has remained unknown, as these variants do not directly alter the UNC13A protein-coding sequence, but are instead located in a region of “junk DNA.”

The researchers found that the risk-linked variants greatly increase the chance of the UNC13A mRNA becoming corrupted once the ALS and FTD disease course has begun. Thus, patients with these genetic variants are likely to suffer greater loss of UNC13A, resulting in more severe disease.

Co-lead author, of the UCL Queen Square Institute of Neurology and Francis Crick Institute, said, “These results represent a significant breakthrough for several reasons. Firstly, they explain why UNC13A genetic variants increase the risk of motor neuron disease and dementia, a question which has puzzled researchers for over a decade. They are also the first to demonstrate a genetic link specifically between loss of nuclear TDP-43 function and ALS, improving scientific understanding of this central disease mechanism.”

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