“Identifying new biomarkers and therapeutic targets for TDP-43 proteinopathies”

Frederick Arnold, PhD
Assistant Professor of Genetics
WashU Medicine

Nuclear depletion and cytoplasmic aggregation of the RNA-binding protein TDP-43 are defining features of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). While TDP-43–dependent splicing regulation is well established, its role in alternative polyadenylation (APA) and 3′ untranslated region (3′UTR) regulation was comparatively understudied until recently. Using RNA-seq datasets from multiple cellular models of TDP-43 dysfunction, combined with neuronal nuclei isolated from postmortem ALS and FTD cortex, we found that loss of nuclear TDP-43 resulted in widespread shifts in polyadenylation site usage, affecting hundreds of genes. These changes were highly enriched among transcripts directly bound by TDP-43 and were characterized predominantly by increased use of distal polyadenylation sites, leading to 3′UTR lengthening.

By characterizing this new category of TDP-43-regulated genes, we have uncovered several new biomarker and therapeutic targets for ALS/FTD and other ‘TDP-43 proteinopathies,’ we were are actively investigating in the lab.