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Frontotemporal Dementia and Related Disorders: Transcriptomic Profiling, Biomarker Discovery, and Mechanistic Insight

Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) lie on a disease spectrum, characterized by overlap in diagnosis, pathology, and underlying genetics. The most prominent of the overlapping genetic causes is a repeat expansion in the gene C9orf72, which is the most common cause of both FTD and ALS. Our study aims to identify the transcriptomic signature of C9orf72-related FTD and ALS by studying post-mortem human brain tissue. Specifically, here we integrated long-read and short-read RNA sequencing data to comprehesively characterize the human frontal cortex, evaluating FTD and ALS patients with the C9orf72 repeat expansion, FTD and ALS patients without the C9orf72 repeat expansion, and controls. Our analysis consisted of transcript classification and annotation, differential gene and transcript analysis, and splicing burden analysis. In total, we found over 1,000 differentially expressed transcripts, including nearly 200 of which that were classified as novel compared to a human reference. Notably, some of these differentially expressed transcripts contained cryptic exons present in genes known to be regulated by TDP-43, like STMN2, while others have not been previously shown (e.g., DRC1). As use to the research community, we have created a shiny application web browser (link: __) that allows for exploration of all transcripts that we detected.