title: Mitochondrial dysfunction and decrease in body weight of a transgenic knock-in mouse model for TDP-43.
abstract: The majority of amyotrophic lateral sclerosis (ALS) cases as well as many patients suffering from frontotemporal lobar dementia (FTLD) with ubiquitinated inclusion bodies show TDP-43 pathology, the protein encoded by the TAR DNA-binding protein (Tardbp) gene. We used recombinase-mediated cassette exchange to introduce an ALS patient cDNA into the mouse Tdp-43 locus. Expression levels of human A315T TDP-43 protein were 300% elevated in heterozygotes, whereas the endogenous mouse Tdp-43 was decreased to 20% of wild type levels as a result of disturbed feedback regulation. Heterozygous TDP-43(A315TKi) mutants lost 10% of their body weight and developed insoluble TDP-43 protein starting as early as 3 months after birth, a pathology that was exacerbated with age. We analyzed the splicing patterns of known Tdp-43 target genes as well as genome-wide gene expression levels in different tissues that indicated mitochondrial dysfunction. In heterozygous mutant animals, we observed a relative decrease in expression of Parkin (Park2) and the fatty acid transporter CD36 along with an increase in fatty acids, HDL cholesterol, and glucose in the blood. As seen in transmission electron microscopy, neuronal cells in motor cortices of TDP-43(A315TKi) animals had abnormal neuronal mitochondrial cristae formation. Motor neurons were reduced to 90%, but only slight motoric impairment was detected. The observed phenotype was interpreted as a predisease model, which might be valuable for the identification of further environmental or genetic triggers of neurodegeneration.
authors: Helmholtz Zentrum München, Institute of Developmental Genetics, Ingolstädter Landstrasse 1, 85764 Neuherberg, Germany.
authors: Carola
authors: C
authors: Stribl
authors: Helmholtz Zentrum München, Institute of Developmental Genetics, Ingolstädter Landstrasse 1, 85764 Neuherberg, Germany.
authors: Aladin
authors: A
authors: Samara
authors: Helmholtz Zentrum München, Institute of Developmental Genetics, Ingolstädter Landstrasse 1, 85764 Neuherberg, Germany.
authors: Dietrich
authors: D
authors: Trümbach
authors: Helmholtz Zentrum München, Institute of Developmental Genetics, Ingolstädter Landstrasse 1, 85764 Neuherberg, Germany.
authors: Regina
authors: R
authors: Peis
authors: Institute of Neuropathology, Schmelzbergstrasse 12, CH-8091 Zurich, Switzerland.
authors: Manuela
authors: M
authors: Neumann
authors: Institute of Experimental Genetics, German Mouse Clinic, Helmholtz Zentrum München, Ingolstaedter Landstrasse 1, 85764 Neuherberg, Germany.
authors: Helmut
authors: H
authors: Fuchs
authors: Institute of Experimental Genetics, German Mouse Clinic, Helmholtz Zentrum München, Ingolstaedter Landstrasse 1, 85764 Neuherberg, Germany.
authors: Valerie
authors: V
authors: Gailus-Durner
authors: Institute of Experimental Genetics, German Mouse Clinic, Helmholtz Zentrum München, Ingolstaedter Landstrasse 1, 85764 Neuherberg, Germany; Technische Universität München, c/o Helmholtz Zentrum München, 85764 Neuherberg, Germany; German Center for Vertigo and Balance Disorders, Ludwig-Maximilians-Universität, Ziemssenstrasse 1a, 80336 Munich, Germany.
authors: Martin
authors: M
authors: Hrabě de Angelis
authors: Institute of Experimental Genetics, German Mouse Clinic, Helmholtz Zentrum München, Ingolstaedter Landstrasse 1, 85764 Neuherberg, Germany; Gene Center, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.
authors: Birgit
authors: B
authors: Rathkolb
authors: Gene Center, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.
authors: Eckhard
authors: E
authors: Wolf
authors: Institute of Experimental Genetics, German Mouse Clinic, Helmholtz Zentrum München, Ingolstaedter Landstrasse 1, 85764 Neuherberg, Germany; Technische Universität München, c/o Helmholtz Zentrum München, 85764 Neuherberg, Germany.
authors: Johannes
authors: J
authors: Beckers
authors: Institute of Experimental Genetics, German Mouse Clinic, Helmholtz Zentrum München, Ingolstaedter Landstrasse 1, 85764 Neuherberg, Germany.
authors: Marion
authors: M
authors: Horsch
authors: Institute of Pathology, German Mouse Clinic, Helmholtz Zentrum München, Ingolstaedter Landstrasse 1, 85764 Neuherberg, Germany.
authors: Frauke
authors: F
authors: Neff
authors: Helmholtz Institut für Molekulare Immunologie (IMI), Helmholtz Zentrum München, 85764 Neuherberg, Germany.
authors: Elisabeth
authors: E
authors: Kremmer
authors: Buchmann Institute for Molecular Life Sciences, Mitochondrial Biology, Max-von-Laue-Strasse 15, 60438 Frankfurt am Main, Germany; Mitochondriale Biologie, Zentrum für Molekulare Medizin, Goethe Universität Frankfurt am Main, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.
authors: Sebastian
authors: S
authors: Koob
authors: Buchmann Institute for Molecular Life Sciences, Mitochondrial Biology, Max-von-Laue-Strasse 15, 60438 Frankfurt am Main, Germany; Mitochondriale Biologie, Zentrum für Molekulare Medizin, Goethe Universität Frankfurt am Main, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany; Mitochondriale Biologie, Zentrum für Molekulare Medizin, Goethe Universität Frankfurt am Main, Max-von-Laue-Strasse 15, 60438 Frankfurt am Main, Germany.
authors: Andreas S
authors: AS
authors: Reichert
authors: Institute of Experimental Genetics, German Mouse Clinic, Helmholtz Zentrum München, Ingolstaedter Landstrasse 1, 85764 Neuherberg, Germany; Molecular Nutritional Medicine, Else Kröner Fresenius Center and ZIEL Research Center for Nutrition and Food Science, Technische Universität München, Gregor-Mendel-Strasse 2, 85350 Freising-Weihenstephan, Germany.
authors: Wolfgang
authors: W
authors: Hans
authors: Institute of Experimental Genetics, German Mouse Clinic, Helmholtz Zentrum München, Ingolstaedter Landstrasse 1, 85764 Neuherberg, Germany; Molecular Nutritional Medicine, Else Kröner Fresenius Center and ZIEL Research Center for Nutrition and Food Science, Technische Universität München, Gregor-Mendel-Strasse 2, 85350 Freising-Weihenstephan, Germany.
authors: Jan
authors: J
authors: Rozman
authors: Molecular Nutritional Medicine, Else Kröner Fresenius Center and ZIEL Research Center for Nutrition and Food Science, Technische Universität München, Gregor-Mendel-Strasse 2, 85350 Freising-Weihenstephan, Germany.
authors: Martin
authors: M
authors: Klingenspor
authors: Research Unit Analytical Pathology, Institute of Pathology, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
authors: Michaela
authors: M
authors: Aichler
authors: Research Unit Analytical Pathology, Institute of Pathology, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
authors: Axel Karl
authors: AK
authors: Walch
authors: Institute of Experimental Genetics, German Mouse Clinic, Helmholtz Zentrum München, Ingolstaedter Landstrasse 1, 85764 Neuherberg, Germany; Department of Neurology, Friedrich-Baur-Institute, Ludwig-Maximilians-Universität, Ziemssenstrasse 1a, 80336 Munich, Germany.
authors: Lore
authors: L
authors: Becker
authors: Research Unit Analytical Pathology, Institute of Pathology, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Department of Neurology, Friedrich-Baur-Institute, Ludwig-Maximilians-Universität, Ziemssenstrasse 1a, 80336 Munich, Germany; Deutsches Zentrum für Neurodegenerative Erkrankungen e. V. (DZNE), Site Munich, Schillerstrasse 44, D-80336 Munich, Germany.
authors: Thomas
authors: T
authors: Klopstock
authors: Helmholtz Zentrum München, Institute of Developmental Genetics, Ingolstädter Landstrasse 1, 85764 Neuherberg, Germany.
authors: Lisa
authors: L
authors: Glasl
authors: Helmholtz Zentrum München, Institute of Developmental Genetics, Ingolstädter Landstrasse 1, 85764 Neuherberg, Germany; Technische Universität München, c/o Helmholtz Zentrum München, 85764 Neuherberg, Germany.
authors: Sabine M
authors: SM
authors: Hölter
authors: Helmholtz Zentrum München, Institute of Developmental Genetics, Ingolstädter Landstrasse 1, 85764 Neuherberg, Germany; Technische Universität München, c/o Helmholtz Zentrum München, 85764 Neuherberg, Germany; Deutsches Zentrum für Neurodegenerative Erkrankungen e. V. (DZNE), Site Munich, Schillerstrasse 44, D-80336 Munich, Germany; Max-Planck-Institute of Psychiatry, Kraepelinstrasse 2-10, 80804 München, Germany.
authors: Wolfgang
authors: W
authors: Wurst
authors: Helmholtz Zentrum München, Institute of Developmental Genetics, Ingolstädter Landstrasse 1, 85764 Neuherberg, Germany; Technische Universität München, c/o Helmholtz Zentrum München, 85764 Neuherberg, Germany. Electronic address: tfloss@helmholtz-muenchen.de.
authors: Thomas
authors: T
authors: Floss
mesh_terms: D000483:Alleles; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001522:Behavior, Animal; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight; D018955:CD36 Antigens / Q000378:metabolism; D008076:Cholesterol, HDL / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000166:cytology; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D055879:Gene Knock-In Techniques; D016678:Genome; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D008297:Male; D018782:Maze Learning; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000473:pathology*; D009046:Motor Neurons / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D010641:Phenotype; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D018955:CD36 Antigens; D008076:Cholesterol, HDL; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D005227:Fatty Acids; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein
keywords: Amyotrophic Lateral Sclerosis (Lou Gehrig's Disease); Mitochondrial Metabolism; Mouse Genetics; Mutagenesis Site-specific; Neurological Diseases