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  • Loss of ALS-associated TDP-43 in zebrafish causes muscle degeneration, vascular dysfunction, and reduced motor neuron axon outgrowth.

Loss of ALS-associated TDP-43 in zebrafish causes muscle degeneration, vascular dysfunction, and reduced motor neuron axon outgrowth.

Proceedings of the National Academy of Sciences of the United States of America (2013-03-05)
Bettina Schmid, Alexander Hruscha, Sebastian Hogl, Julia Banzhaf-Strathmann, Katrin Strecker, Julie van der Zee, Mathias Teucke, Stefan Eimer, Jan Hegermann, Maike Kittelmann, Elisabeth Kremmer, Marc Cruts, Barbara Solchenberger, Laura Hasenkamp, Frauke van Bebber, Christine Van Broeckhoven, Dieter Edbauer, Stefan F Lichtenthaler, Christian Haass
ABSTRACT

Mutations in the Tar DNA binding protein of 43 kDa (TDP-43; TARDBP) are associated with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TDP-43(+) inclusions (FTLD-TDP). To determine the physiological function of TDP-43, we knocked out zebrafish Tardbp and its paralogue Tardbp (TAR DNA binding protein-like), which lacks the glycine-rich domain where ALS- and FTLD-TDP-associated mutations cluster. tardbp mutants show no phenotype, a result of compensation by a unique splice variant of tardbpl that additionally contains a C-terminal elongation highly homologous to the glycine-rich domain of tardbp. Double-homozygous mutants of tardbp and tardbpl show muscle degeneration, strongly reduced blood circulation, mispatterning of vessels, impaired spinal motor neuron axon outgrowth, and early death. In double mutants the muscle-specific actin binding protein Filamin Ca is up-regulated. Strikingly, Filamin C is similarly increased in the frontal cortex of FTLD-TDP patients, suggesting aberrant expression in smooth muscle cells and TDP-43 loss-of-function as one underlying disease mechanism.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
CompoZr Custom Zinc Finger Nuclease (ZFN), ZFN plasmid only
Sigma-Aldrich
CompoZr® Custom Zinc Finger Nuclease (ZFN), ZFN plasmid and mRNA