In a paper in press in Brain Research, researchers have given one mouse model of TDP-43 proteinopathy a thumbs-down. While it was the first such mouse to be published (see Oct 2009 news story), it fails to mimic key features of amyotrophic lateral sclerosis, and it dies of unrelated symptoms—neurodegeneration in the colon leading to fatal bowel obstruction, as reported previously on Alzforum (see Sep 2012 feature story). “While this mouse may be useful for studying gastrointestinal tract neurodegeneration, in its present state it does not display a phenotype suitable for testing ALS therapeutics,” concluded the study authors, including joint senior authors Steve Perrin at the ALS Therapy Development Institute (ALS-TDI) in Cambridge, Massachusetts, and Cat Lutz from the Jackson Laboratory (JAX) in Bar Harbor, Maine.

The mice were originally bred on a hybrid background, as is standard, but joint first authors Theo Hatzipetros at ALS-TDI and Laurent Bogdanik at JAX backcrossed them to a pure line, creating more than 650 mice for analysis. This backcross eliminated many ALS-like features seen in the original mice. The pure strain walked normally with no signs of paralysis, though they did tend to drag their tails a bit.

The scientists investigated the gut phenotype and determined it was due to overexpression of the TDP-43 transgene in the myenteric plexus, a bundle of nerve fibers in the gut, which degenerated. This led to a digestive slowdown, killing the mice.—Amber Dance.
References:
Hatzipetros T, Bogdanik LP, Tassinari VR, Kidd JD, Moreno AJ, Davis C, Osborne M, Austin A, Vieira FG, Lutz C, Perrin S. C57BL/6J congenic Prp-TDP43A315T mice develop progressive neurodegeneration in the myenteric plexus of the colon without exhibiting key features of ALS. Brain Res. 2013 Oct 18. Abstract

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References

News Citations

  1. Meet the First Published TDP-43 Mouse

Paper Citations

  1. . C57BL/6J congenic Prp-TDP43A315T mice develop progressive neurodegeneration in the myenteric plexus of the colon without exhibiting key features of ALS. Brain Res. 2013 Oct 18; PubMed.

Other Citations

  1. Sep 2012 feature story

Further Reading

Papers

  1. . 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. PubMed.
  2. . TDP-43-based animal models of neurodegeneration: new insights into ALS pathology and pathophysiology. Neurodegener Dis. 2011;8(4):262-74. PubMed.
  3. . Expression of mutant TDP-43 induces neuronal dysfunction in transgenic mice. Mol Neurodegener. 2011;6:73. PubMed.
  4. . HO-1 induction in motor cortex and intestinal dysfunction in TDP-43 A315T transgenic mice. Brain Res. 2012 Jun 15;1460:88-95. PubMed.
  5. . TDP-43 functions and pathogenic mechanisms implicated in TDP-43 proteinopathies. Trends Mol Med. 2011 Nov;17(11):659-67. PubMed.
  6. . Progressive motor weakness in transgenic mice expressing human TDP-43. Neurobiol Dis. 2010 Nov;40(2):404-14. PubMed.
  7. . C57BL/6J congenic Prp-TDP43A315T mice develop progressive neurodegeneration in the myenteric plexus of the colon without exhibiting key features of ALS. Brain Res. 2013 Oct 18; PubMed.

Primary Papers

  1. . C57BL/6J congenic Prp-TDP43A315T mice develop progressive neurodegeneration in the myenteric plexus of the colon without exhibiting key features of ALS. Brain Res. 2013 Oct 18; PubMed.