Tdp-43 cryptic exons are highly variable between cell types.
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.



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.



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.



Our results suggest that in human disease, TDP-43 loss of function may impair cell type-specific pathways.
Departments of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.|Neural Development and Disease Department, Korea Brain Research Institute, Daegu, 701-300, South Korea.
Yun Ha
YH
Jeong
Departments of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
Jonathan P
JP
Ling
Departments of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
Sophie Z
SZ
Lin
Departments of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.|Departments of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
Aneesh N
AN
Donde
Departments of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
Kerstin E
KE
Braunstein
Laboratory of Neurogenetics, NIA, NIH, Bethesda, MD, 20892, USA.|Present address: Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University School of Medicine, Cardiff, CF24 4HQ, UK.
Elisa
E
Majounie
Departments of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.|Laboratory of Neurogenetics, NIA, NIH, Bethesda, MD, 20892, USA.
Bryan J
BJ
Traynor
Departments of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
Katherine D
KD
LaClair
Departments of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.|Departments of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
Thomas E
TE
Lloyd
Departments of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. wong@jhmi.edu.|Departments of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. wong@jhmi.edu.
Philip C
PC
Wong
D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics*; D004195:Disease Models, Animal; D005091:Exons / Q000235:genetics*; D015151:Immunoblotting; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D032342:Muscle Cells / Q000378:metabolism*; D018485:Muscle Fibers, Skeletal / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D057177:TDP-43 Proteinopathies / Q000235:genetics
D004268:DNA-Binding Proteins; C578077:Tardbp protein, mouse
Amyotrophic lateral sclerosis; Bioinformatics; Frontotemporal dementia; Inclusion body myositis; TDP-43 –Nonconserved cryptic exons