Journal Article

Tdp-43 cryptic exons are highly variable between cell types

LaClair, Katherine D., Lloyd, Thomas E., Donde, Aneesh N., Traynor, Bryan J., Wong, Philip C., Majounie, Elisa, Ling, Jonathan P., Braunstein, Kerstin E., Jeong, Yun Ha, Lin, Sophie Z.

2017

Overview

Background TDP-43 proteinopathy is a prominent pathological feature that occurs in a number of human diseases including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and inclusion body myositis (IBM). Our recent finding that TDP-43 represses nonconserved cryptic exons led us to ask whether cell type-specific cryptic exons could exist to impact unique molecular pathways in brain or muscle. Methods In the present work, we investigated TDP-43’s function in various mouse tissues to model disease pathogenesis. We generated mice to conditionally delete TDP-43 in excitatory neurons or skeletal myocytes and identified the cell type-specific cryptic exons associated with TDP-43 loss of function. Results Comparative analysis of nonconserved cryptic exons in various mouse cell types revealed that only some cryptic exons were common amongst stem cells, neurons, and myocytes; the majority of these nonconserved cryptic exons were cell type-specific. Conclusions Our results suggest that in human disease, TDP-43 loss of function may impair cell type-specific pathways.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V
• Subject: Amyotrophic lateral sclerosis / Animals / Biomedical and Life Sciences / Biomedicine / Diagnosis / Disease Models, Animal / DNA-Binding Proteins - genetics / Exons (Molecular genetics) / Exons - genetics / Genetic aspects / Immunoblotting / Immunohistochemistry / Mice / Mice, Knockout / Mice, Transgenic / Molecular Medicine / Muscle Cells - metabolism / Muscle Fibers, Skeletal - metabolism / Neurology / Neurons / Neurons - metabolism / Neurosciences / Physiological aspects / Research Article / Reverse Transcriptase Polymerase Chain Reaction / Risk factors / TDP-43 Proteinopathies - genetics