A team of researchers from University College London (UCL), UK, has found why a common genetic variant represents a worse outcome for some patients diagnosed with neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD).
Published in Nature (1), the main results show how depletion of a protein called TDP-43 — which is associated with virtually all cases of ALS and FTD — corrupts genetic instructions to make another protein called UNC13A. In practical terms, as UNC13A is vital to ensure that neurons can communicate with each other, this means more severe cases of ALS and FTD for the patients have have a common genetic variant.
“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,” said author Dr. Michael Ward from the National Institute of Neurological Disorders and Stroke, NIH, US.
ALS is the most common motor neuron disease and, at the moment, there is no cure. This condition affects the brain and spinal cord by killing the nerve cells that control movement. There is only one drug approved for ALS, but it only expands life for a few months, and it only works for a small proportion of patients. FTD is not as common as ALS but is a related disease with similar causes. Symptoms include language problems, personality changes, and cognitive issues.
The most important protein in ALS is TDP-43. In many cases of ALS and about half of the FTD cases, the problem starts when TDP-43 is removed from the cell’s nucleus. Inevitably, the protein can no longer perform its functions, including making sure mRNA is produced accurately. One of the proteins affected is UNC13A. Given the crucial role that UNC13A plays in neuron communication, losing this protein likely leads to more severe cases. The authors also observed that some mutations in UNC13A — which are common, even in people that don’t have the disease — result in greater losses of this protein. Patients with these genetic variants are more likely to suffer more severe diseases.
“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 that 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,” said author, PhD student Oscar Wilkins, from UCL Queen Square Institute of Neurology and Francis Crick Institute.
The authors believe this work may lead to new treatments, including developing a therapy that stops TDP-43, which may slow down disease progression for most patients with ALS and about half of the patients with FTD.
(1) Brown, AL., Wilkins, O.G., Keuss, M.J. et al. TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A. Nature (2022). https://doi.org/10.1038/s41586-022-04436-3