Journal
MOLECULAR NEURODEGENERATION
Volume 12, Issue -, Pages -Publisher
BMC
DOI: 10.1186/s13024-016-0144-x
Keywords
TDP-43-Nonconserved cryptic exons; Bioinformatics; Amyotrophic lateral sclerosis; Frontotemporal dementia; Inclusion body myositis
Categories
Funding
- Robert Packard Center for ALS Research
- Amyotrophic Lateral Sclerosis Association
- Target ALS
- JHU Neuropathology Pelda fund
- DoD grant [W81XWH1110449]
- Korea Brain Research Institute basic research program Grant [2231-415]
- McKnight Memory and Cognitive Disorders Award
- NIH grant [R01-NS095969]
- U.S. Department of Defense (DOD) [W81XWH1110449] Funding Source: U.S. Department of Defense (DOD)
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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.
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