title: Loss of ALS-associated TDP-43 in zebrafish causes muscle degeneration, vascular dysfunction, and reduced motor neuron axon outgrowth.
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.
authors: German Center for Neurodegenerative Diseases, 80336 Munich, Germany. beschmid@med.uni-muenchen.de
authors: Bettina
authors: B
authors: Schmid
authors: Alexander
authors: A
authors: Hruscha
authors: Sebastian
authors: S
authors: Hogl
authors: Julia
authors: J
authors: Banzhaf-Strathmann
authors: Katrin
authors: K
authors: Strecker
authors: Julie
authors: J
authors: van der Zee
authors: Mathias
authors: M
authors: Teucke
authors: Stefan
authors: S
authors: Eimer
authors: Jan
authors: J
authors: Hegermann
authors: Maike
authors: M
authors: Kittelmann
authors: Elisabeth
authors: E
authors: Kremmer
authors: Marc
authors: M
authors: Cruts
authors: Barbara
authors: B
authors: Solchenberger
authors: Laura
authors: L
authors: Hasenkamp
authors: Frauke
authors: F
authors: van Bebber
authors: Christine
authors: C
authors: Van Broeckhoven
authors: Dieter
authors: D
authors: Edbauer
authors: Stefan F
authors: SF
authors: Lichtenthaler
authors: Christian
authors: C
authors: Haass
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001369:Axons / Q000378:metabolism* / Q000473:pathology; D003285:Contractile Proteins / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins; D064448:Filamins; D006801:Humans; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D009046:Motor Neurons / Q000378:metabolism* / Q000473:pathology; D009133:Muscular Atrophy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009154:Mutation; D017434:Protein Structure, Tertiary; D014652:Vascular Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015027:Zebrafish / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D003285:Contractile Proteins; D004268:DNA-Binding Proteins; D064448:Filamins; D008840:Microfilament Proteins; D029961:Zebrafish Proteins