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Schmid, B.* ; Hruscha, A.* ; Högl, 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.* ; 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. 110, 4986-4991 (2013)
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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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Neurodegeneration ; Zinc Finger Nuclease ; Proteomics; Amyotrophic-lateral-sclerosis ; Frontotemporal Lobar Degeneration ; Myofibrillar Myopathy ; Rna Targets ; Blood-flow ; In-vivo ; Filamin ; Mutations ; Expression ; Depletion
Language english
Publication Year 2013
HGF-reported in Year 2013
ISSN (print) / ISBN 0027-8424
e-ISSN 1091-6490
Journal Proceedings of the National Academy of Sciences of the United States of America
Quellenangaben Volume: 110, Issue: 13, Pages: 4986-4991 Article Number: , Supplement: ,
Publisher National Academy of Sciences
Reviewing status Peer reviewed
Institute(s) Institute of Molecular Immunology (IMI)
POF-Topic(s) 30504 - Mechanisms of Genetic and Environmental Influences on Health and Disease
Research field(s) Immune Response and Infection
PSP Element(s) G-501793-001
PubMed ID 23457265
DOI 10.1073/pnas.1218311110
WOS ID WOS:000318031900036
Scopus ID 84875508368
Erfassungsdatum 2013-05-31
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