Journal Article

DZNE-2023-00700

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Loss of TDP-43 causes ectopic endothelial sprouting and migration defects through increased fibronectin, vcam 1 and integrin α4/β1.

Hipke, K. (First author)DZNE* ; Pitter, B. ; Hruscha, A.DZNE* ; van Bebber, F.DZNE* ; Modic, M. ; Bansal, V.DZNE* ; Lewandowski, S. A. ; Orozco, D.DZNE* ; Edbauer, D.DZNE* ; Bonn, S. ; Haass, C.DZNE* ; Pohl, U. ; Montanez, E. ; Schmid, B. (Last author)DZNE*

2023
Frontiers Media Lausanne

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Please use a persistent id in citations: doi:10.3389/fcell.2023.1169962

Abstract: Aggregation of the Tar DNA-binding protein of 43 kDa (TDP-43) is a pathological hallmark of amyotrophic lateral sclerosis and frontotemporal dementia and likely contributes to disease by loss of nuclear function. Analysis of TDP-43 function in knockout zebrafish identified an endothelial directional migration and hypersprouting phenotype during development prior lethality. In human umbilical vein cells (HUVEC) the loss of TDP-43 leads to hyperbranching. We identified elevated expression of FIBRONECTIN 1 (FN1), the VASCULAR CELL ADHESION MOLECULE 1 (VCAM1), as well as their receptor INTEGRIN α4β1 (ITGA4B1) in HUVEC cells. Importantly, reducing the levels of ITGA4, FN1, and VCAM1 homologues in the TDP-43 loss-of-function zebrafish rescues the angiogenic defects indicating the conservation of human and zebrafish TDP-43 function during angiogenesis. Our study identifies a novel pathway regulated by TDP-43 important for angiogenesis during development.

Keyword(s): ALS ; TDP-43 ; angiogenesis ; neurodegeneration ; zebrafish

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Contributing Institute(s):

1. Fish Core Unit (AG Schmid)
2. Biomedical Data Science (AG Bansal)
3. Cell Biology of Neurodegeneration (AG Edbauer)
4. Molecular Neurodegeneration (AG Haass)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)
2. 354 - Disease Prevention and Healthy Aging (POF4-354) (POF4-354)

Appears in the scientific report 2023

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