Genetic variants increase the risk of UNC13A mRNA corruption Given the essential role UNC13A plays in facilitating neuron communication, its corruption is thus likely to impair neuronal function and contribute to neurodegeneration in those with ALS and FTD. Furthermore, when the team looked at ALS and FTD patient brain samples, they again found that the mRNAs for UNC13A were incorrect, confirming that their experiments replicated the real-world disease process. They found that the mRNAs for the UNC13A protein were corrupted, meaning the ribosomes in the lab-grown neurons were unable to correctly produce the UNC13A protein.
The scientists were then able to study how these neurons without TDP-43 differed from healthy neurons.
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But we haven’t known how to reverse the most problematic consequences of TDP-43 loss.”Īs 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, the Nobel-prize winning gene-editing technology. This prevents TDP-43 from performing its important functions, such as ensuring that mRNA is produced correctly.ĭr Ward said: “We have known for a long time that most patients with ALS, and about half of FTD patients, lose the function of a key protein called TDP-43, wreaking havoc in nerve cells that are affected. 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.”Īrguably the most important protein in ALS research is TDP-43, as in most cases (as well as half of FTD cases), the protein is incorrectly ejected from the cell’s nucleus. Researchers say the discovery raises hope for new treatments by developing a therapy that blocks the corruption of UNC13A’s genetic instructions, disease progression could be slowed for most people with ALS and around half of patients with FTD.Ĭorresponding author Professor Pietro Fratta (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.”Ĭo-corresponding author Dr Michael Ward (National Institute of Neurological Disorders and Stroke, NIH, US) added: “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. One third of patients die within one year of diagnosis.įTD is a related disease with similar underlying causes symptoms include language impairment, changes in personality and cognitive difficulties. There is currently only one approved drug for ALS in the UK, which extends lifespan by a few months, and is only effective for a tiny minority of patients. The researchers believe that the corruption of UNC13A’s genetic instructions in patients may have similarly harmful consequences.ĪLS is the most common motor neuron disease and there is no known cure it affects the brain and spinal cord by attacking the neurons and nerves which control movement, causing them to die. UNC13A enables neurons (nerve cells) to communicate with each other via neurotransmitter release, and data from animal models suggests its loss from neurons can be fatal. Strikingly, it found that a mysterious genetic variant previously associated with disease risk increases the chance of UNC13A’s genetic instructions being corrupted among people with the diseases, thereby worsening risk and severity of ALS and FTD. Published in Nature, the study shows how TDP-43 protein depletion, associated with almost all cases (97%) of ALS and half of FTD cases, corrupts the genetic instructions for the critical neuronal protein UNC13A. A pioneering new study led by UCL and National Institutes of Health (NIH) scientists has revealed, for the first time, why a common genetic variant worsens disease outcomes for people with the devastating adult-onset neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
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