Alzforum previously reported Schmid and Haass’ meeting presentations, in which they reported that they only achieved a mutant phenotype when they eliminated both fish versions of the gene, TARDBP and “TARDBP-like.” Double-mutant embryos survive for just a week (see ARF related news story; ARF news story). Human TDP-43 rescues the TARDBP-deficient fish, but Schmid and Haass now add that an ALS-linked mutation, glycine-348-cysteine, saves some knockout embryos. This indicates that while a total loss of TARDBP is indeed lethal, a mild mutation can support life for a short time. “We therefore hypothesize that a subtle loss of function … leads over time to ALS and FTLD-TDP pathology,” the authors suggest.

In the paper, the team added an analysis of the proteome created by TARDBP loss. Thirteen proteins were upregulated and 28 downregulated in the double knockouts. Most of the latter were muscle based, fitting with that phenotype. The top upregulated hit was the muscle protein filamin C, with doubled levels in the knockouts. Human filamin C was upregulated in brains from people with FTLD due to TDP-43 proteinopathy, but not Alzheimer’s or neurologically healthy samples.

Filamin C crosslinks actin in multiple types of muscle, including those surrounding blood vessels in the brain. The authors hypothesize that in cases of TDP-43 proteinopathy, an excess of filamin C diminishes blood flow in the brain, and results in the leaky blood-brain barrier and blood-spinal cord barrier observed in people with ALS (Winkler et al., 2012; Ishikawa et al., 2007).—Amber Dance.

Reference:
Schmid B, Hruscha A, Hogl S, Banzhaf-Strathmann J, Strecker K, van der Zee J, Teucke M, Eimer S, Hegermann J, Kittelmann M, Kremmer E, Cruts M, Solchenberger B, Hasenkamp L, van Bebber F, Van Broeckhoven C, Edbauer D, Lichtenthaler SF, Haass C. Loss of ALS-associated TDP-43 in zebrafish causes muscle degeneration, vascular dysfunction, and reduced motor neuron axon outgrowth. Proc Natl Acad Sci U S A. 2013 Mar 1. Abstract