Understanding the causes and consequences of TAR DNA-binding protein 43 (TDP-43) aggregation is a key research focus, given its occurrence in more than 97% of amyotrophic lateral sclerosis (ALS) cases and 45% of frontotemporal dementia (FTD) cases. Cytoplasmic relocalization and aggregation of TDP-43 prevents its activity as a regulator of mRNA splicing, which can lead to mis-splicing events and the improper inclusion of intronic sequences in mature mRNA transcripts. Matthew Keuss, PhD, UCL Queen Square Institute of Neurology, University College London, London, discusses findings from a study assessing how this process impacts UNC13A, a gene that has been associated with ALS and FTD in genome wide association studies. RNA sequencing data identified a cryptic exon in UNC13A that leads to the inclusion of an intronic SNP known to be associated with increased disease risk. It was also shown that the UNC13A risk SNPs lead to an increased probability of cryptic exon inclusion and thus, UNC13A depletion. These findings demonstrate a link between cryptic exon inclusion and disease risk and highlight UNC13A as a potential target for antisense oligonucleotide therapy. This interview took place at the Alzheimer’s Research UK (ARUK) Conference 2023 in Aberdeen, UK.
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