A pioneering study led by UCL and the National Institutes of Health (NIH) scientists has revealed why a common genetic variant worsens disease outcomes for people with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are devastating adult-onset neurodegenerative disorders with shared genetic causes and common pathological aggregates. Genome-wide association studies (GWAS) have repeatedly demonstrated a shared risk locus for ALS and FTD in the crucial synaptic gene UNC13A.
ALS and FTD are pathologically defined by cytoplasmic aggregation and nuclear depletion of TAR DNA-binding protein 43 (TDP-43) in more than 97% of ALS cases and 45% of FTD cases. TDP-43 is an RNA-binding protein that resides in the nucleus and has key roles in RNA metabolism.
The study was published in the journal Nature, and shows how TDP-43 protein depletion corrupts the genetic instructions for an important neuronal protein called UNC13A. This protein enables neurons to communicate with each other via neurotransmitters, and from animal models it is known that its loss can be fatal for the survival of neurons.
The researchers believe that this discovery could lead to the development of new therapeutic options for ALS and FTD patients, by using a therapy that blocks the corruption of UNC13A genetic instructions.
The team was also able to evaluate their results in humans, by using ALS and FTD patient brain samples, and found again that the mRNAs for UNC13A were incorrect, which confirmed that their results translate to the human model of the disease. They hope to carry out trials to develop a treatment targeting this mechanism.
Emily Henderson, B.Sc. Research reveals why a common genetic variant worsens outcomes for people with ALS and FTD. News Medical Life Sciences. Retrieved from:
Brown, AL., 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