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ARUK 2023 | de novo proteins generated from cryptic exon translation in ALS & FTD

The cytoplasmic relocalization and aggregation of TDP-43 in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD)leads to its depletion in the nucleus, preventing its activity as a regulator of mRNA splicing. The resultant mis-splicing events leads to the improper inclusion of intronic sequences in hundreds of mRNA transcripts, which typically cause degradation of the mRNA. Matthew Keuss, PhD, UCL Queen Square Institute of Neurology, University College London, London, discusses a recent study looking at cases where these cryptic exons generate de novo proteins. Numerous cryptic transcripts identified in TDP-43 depleted iPSC-derived neurons were shown to map to de novo peptides with altered protein interaction profiles. Additionally, proteomic analyses identified these de novo peptides in the cerebrospinal fluid of patients with ALS. Dr Keuss notes the importance this newly generated dataset of de novo peptides so that the research community can investigate their impact in disease and potentially uncover new pathophysiological mechanisms, biomarkers, and therapeutic targets. This interview took place at the Alzheimer’s Research UK (ARUK) Conference 2023 in Aberdeen, UK.

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