Premature death of TDP-43 (A315T) transgenic mice due to gastrointestinal complications prior to development of full neurological symptoms of amyotrophic lateral sclerosis

Int J Exp Pathol. 2013 Feb;94(1):56-64. doi: 10.1111/iep.12006.


Abnormal distribution, modification and aggregation of transactivation response DNA-binding protein 43 (TDP-43) are the hallmarks of multiple neurodegenerative diseases, especially frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) and amyotrophic lateral sclerosis (ALS). Transgenic mouse lines overexpressing wild-type or mutant TDP-43 exhibit ALS-like symptom, motor abnormalities and early paralysis followed by death. Reports on lifespan and phenotypic behaviour in Prp-TDP-43 (A315T) vary, and these animals are not fully characterized. Although it has been proposed that the approximate 20% loss of motor neurons at end stage is responsible for the severe weakness and death in TDP-43 mice, this degree of neurologic damage appears insufficient to cause death. Hence we studied these mice to further characterize and determine the reason for the death. Our characterization of TDP-43 transgenic mice showed that these mice develop ALS-like symptoms that later become compounded by gastrointestinal (GI) complications that resulted in death. This is the first report of a set of pathological evidence in the GI track that is strong indicator for the cause of death of Prp-hTDP-43 (A315T) transgenic mice.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Amyotrophic Lateral Sclerosis / genetics
  • Amyotrophic Lateral Sclerosis / metabolism*
  • Amyotrophic Lateral Sclerosis / pathology
  • Amyotrophic Lateral Sclerosis / physiopathology
  • Animals
  • Behavior, Animal
  • Cecum / metabolism
  • Cecum / pathology
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Disease Progression
  • Female
  • Gastrointestinal Diseases / genetics
  • Gastrointestinal Diseases / metabolism*
  • Gastrointestinal Diseases / pathology
  • Gastrointestinal Diseases / physiopathology
  • Genetic Predisposition to Disease
  • Humans
  • Ileum / metabolism
  • Ileum / pathology
  • Intestinal Mucosa / metabolism*
  • Intestines / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Motor Activity
  • Phenotype
  • Spinal Cord / metabolism*
  • Spinal Cord / pathology


  • DNA-Binding Proteins