Tdp-43 cryptic exons are highly variable between cell types

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

doi:10.1186/s13024-016-0144-x

Abstract

BackgroundTDP-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.MethodsIn 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.ResultsComparative 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.ConclusionsOur results suggest that in human disease, TDP-43 loss of function may impair cell type-specific pathways.

Highlights

Transactive response DNA binding protein 43 kDa (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)
Selective deletion of Tdp-43 in mouse excitatory neurons and skeletal myocytes To identify the cryptic exons repressed by Tdp-43 in neurons and myocytes, we utilized the Cre recombinase system to conditionally delete Tdp-43
Efficient deletion of Tdp-43 can be detected by immunoblot in brain (Fig. 1b) and skeletal muscle (Fig. 1c); residual Tdp-43 in F/F mice reflects the presence of other cell types that do not express Calcium/calmodulin-dependent protein kinase II alpha (CaMKIIα)-Cre or myosin light chain 1/3 locus (MLC)-Cre

Summary

Introduction

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). 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. We have recently found that TDP-43 plays a major role in repressing nonconserved cryptic exons [15]. These cryptic exons are regions of the genome that are normally skipped by the spliceosome due to the presence of adjacent UG microsatellite repeats, the consensus binding site of TDP-43. We found that Tdp-43 cryptic exons are highly variable between cell types and that many distinct pathways are

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Results

Discussion

Conclusion