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Molecular Neurodegeneration

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Open Access 01-12-2014 | Research article

Prevention of intestinal obstruction reveals progressive neurodegeneration in mutant TDP-43 (A315T)mice

Authors: Sarah Herdewyn, Carla Cirillo, Ludo Van Den Bosch, Wim Robberecht, Pieter Vanden Berghe, Philip Van Damme

Published in: Molecular Neurodegeneration | Issue 1/2014

Abstract

Background

Intraneuronal inclusions of TAR DNA-binding protein 43 (TDP-43) have been found in the majority of Amyotrophic Lateral Sclerosis (ALS) patients. Mutations in the gene encoding TDP-43 cause familial ALS. Transgenic mice expressing mutant TDP-43 with one such mutation (TDP-43 (A315T)) under control of the murine prion promoter develop motor symptoms, but their use is currently hampered by sudden death. We aimed to understand and overcome the cause of sudden death in TDP-43 (A315T) mice. Since intestinal obstruction was suspected to be the cause, intestinal motility of TDP-43 (A315T) mice was studied in an ex-vivo pellet propulsion assay. The effect on the enteric and motor phenotype was assessed, both in animals on normal chow or on a jellified fiber deprived diet, aimed at preventing intestinal obstruction.

Results

The frequency of the propulsive motor complexes was significantly reduced in the colon of TDP-43 (A315T) compared to non transgenic (NTG) mice. Immunohistochemistry revealed significant enlargement in size and reduction in number of the nitric oxide synthase (NOS) neurons in the myenteric plexus of TDP-43 (A315T) mice. Prevention of intestinal obstruction by jellified food abolished sudden death, allowing the motor phenotype to develop and slowly progress with a more pronounced degeneration of upper and lower motor axons. A downregulation of endogenous TDP-43 mRNA and protein levels was observed prior to neurodegeneration.

Conclusion

TDP-43 (A315T) mice suffer from intestinal dysmotility due to degeneration of NOS neurons in the myenteric plexus. Feeding the mice jellified food prevents sudden death and allows the motor phenotype to progress.

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Title: Prevention of intestinal obstruction reveals progressive neurodegeneration in mutant TDP-43 (A315T)mice
Authors: Sarah Herdewyn
Carla Cirillo
Ludo Van Den Bosch
Wim Robberecht
Pieter Vanden Berghe
Philip Van Damme
Publication date: 01-12-2014
Publisher: BioMed Central
Published in: Molecular Neurodegeneration / Issue 1/2014
Electronic ISSN: 1750-1326
DOI: https://doi.org/10.1186/1750-1326-9-24

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Prevention of intestinal obstruction reveals progressive neurodegeneration in mutant TDP-43 (A315T)mice

Abstract

Background

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Results

Conclusion

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