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 senior author Steve Perrin at the ALS Therapy Development Institute (ALS-TDI) in Cambridge, Massachusetts, and collaborators 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.
Reference: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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