ZFIN ID: ZDB-PUB-130322-12
Loss of ALS-associated TDP-43 in zebrafish causes muscle degeneration, vascular dysfunction, and reduced motor neuron axon outgrowth
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, S.F., and Haass, C.
Date: 2013
Source: Proceedings of the National Academy of Sciences of the United States of America   110(13): 4986-91 (Journal)
Registered Authors: Haass, Christian, Hasenkamp, Laura, Hruscha, Alexander, Schmid, Bettina, Solchenberger, Barbara, Strecker, Katrin, Teucke, Mathias, van Bebber, Frauke
Keywords: neurodegeneration, zinc finger nuclease, proteomics
MeSH Terms:
  • Amyotrophic Lateral Sclerosis/genetics
  • Amyotrophic Lateral Sclerosis/metabolism
  • Amyotrophic Lateral Sclerosis/pathology
  • Animals
  • Axons/metabolism*
  • Axons/pathology
  • Contractile Proteins/genetics
  • Contractile Proteins/metabolism
  • DNA-Binding Proteins*
  • Filamins
  • Humans
  • Microfilament Proteins/genetics
  • Microfilament Proteins/metabolism
  • Motor Neurons/metabolism*
  • Motor Neurons/pathology
  • Muscular Atrophy/genetics
  • Muscular Atrophy/metabolism*
  • Muscular Atrophy/pathology
  • Mutation*
  • Protein Structure, Tertiary
  • Vascular Diseases/genetics
  • Vascular Diseases/metabolism*
  • Vascular Diseases/pathology
  • Zebrafish/metabolism*
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
PubMed: 23457265 Full text @ Proc. Natl. Acad. Sci. USA

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.