TY  - JOUR
AU  - Hu, Yiying
AU  - Hruscha, Alexander
AU  - Pan, Chenchen
AU  - Schifferer, Martina
AU  - Schmidt, Michael K
AU  - Nuscher, Brigitte
AU  - Giera, Martin
AU  - Kostidis, Sarantos
AU  - Burhan, Özge
AU  - van Bebber, Frauke
AU  - Edbauer, Dieter
AU  - Arzberger, Thomas
AU  - Haass, Christian
AU  - Schmid, Bettina
TI  - Mis-localization of endogenous TDP-43 leads to ALS-like early-stage metabolic dysfunction and progressive motor deficits.
JO  - Molecular neurodegeneration
VL  - 19
IS  - 1
SN  - 1750-1326
CY  - London
PB  - Biomed Central
M1  - DZNE-2024-00796
SP  - 50
PY  - 2024
AB  - The key pathological signature of ALS/ FTLD is the mis-localization of endogenous TDP-43 from the nucleus to the cytoplasm. However, TDP-43 gain of function in the cytoplasm is still poorly understood since TDP-43 animal models recapitulating mis-localization of endogenous TDP-43 from the nucleus to the cytoplasm are missing.CRISPR/Cas9 technology was used to generate a zebrafish line (called CytoTDP), that mis-locates endogenous TDP-43 from the nucleus to the cytoplasm. Phenotypic characterization of motor neurons and the neuromuscular junction was performed by immunostaining, microglia were immunohistochemically localized by whole-mount tissue clearing and muscle ultrastructure was analyzed by scanning electron microscopy. Behavior was investigated by video tracking and quantitative analysis of swimming parameters. RNA sequencing was used to identify mis-regulated pathways with validation by molecular analysis.CytoTDP fish have early larval phenotypes resembling clinical features of ALS such as progressive motor defects, neurodegeneration and muscle atrophy. Taking advantage of zebrafish's embryonic development that solely relys on yolk usage until 5 days post fertilization, we demonstrated that microglia proliferation and activation in the hypothalamus is independent from food intake. By comparing CytoTDP to a previously generated TDP-43 knockout line, transcriptomic analyses revealed that mis-localization of endogenous TDP-43, rather than TDP-43 nuclear loss of function, leads to early onset metabolic dysfunction.The new TDP-43 model mimics the ALS/FTLD hallmark of progressive motor dysfunction. Our results suggest that functional deficits of the hypothalamus, the metabolic regulatory center, might be the primary cause of weight loss in ALS patients. Cytoplasmic gain of function of endogenous TDP-43 leads to metabolic dysfunction in vivo that are reminiscent of early ALS clinical non-motor metabolic alterations. Thus, the CytoTDP zebrafish model offers a unique opportunity to identify mis-regulated targets for therapeutic intervention early in disease progression.
KW  - Animals
KW  - Zebrafish
KW  - Amyotrophic Lateral Sclerosis: metabolism
KW  - Amyotrophic Lateral Sclerosis: pathology
KW  - Amyotrophic Lateral Sclerosis: genetics
KW  - DNA-Binding Proteins: metabolism
KW  - DNA-Binding Proteins: genetics
KW  - Disease Models, Animal
KW  - Motor Neurons: metabolism
KW  - Motor Neurons: pathology
KW  - Zebrafish Proteins: metabolism
KW  - Zebrafish Proteins: genetics
KW  - Animals, Genetically Modified
KW  - Neuromuscular Junction: metabolism
KW  - Neuromuscular Junction: pathology
KW  - ALS (Other)
KW  - Animal model (Other)
KW  - Hypothalamus (Other)
KW  - Metabolic dysfunction (Other)
KW  - Neurodegeneration (Other)
KW  - TDP-43 (Other)
KW  - Zebrafish (Other)
KW  - DNA-Binding Proteins (NLM Chemicals)
KW  - Zebrafish Proteins (NLM Chemicals)
KW  - Tardbp protein, zebrafish (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C2  - pmc:PMC11188230
C6  - pmid:38902734
DO  - DOI:10.1186/s13024-024-00735-7
UR  - https://pub.dzne.de/record/270416
ER  -