Mitochondrial dysfunction and decrease in body weight of a transgenic knock-in mouse model for TDP-43

Carola Stribl, Aladin Samara, Dietrich Trümbach, Regina Peis, Manuela Neumann, Helmut Fuchs, Valerie Gailus-Durner, Martin Hrabě De Angelis, Birgit Rathkolb, Eckhard Wolf, Johannes Beckers, Marion Horsch, Frauke Neff, Elisabeth Kremmer, Sebastian Koob, Andreas S. Reichert, Wolfgang Hans, Jan Rozman, Martin Klingenspor, Michaela AichlerAxel Karl Walch, Lore Becker, Thomas Klopstock, Lisa Glasl, Sabine M. Hölter, Wolfgang Wurst, Thomas Floss

Research output: Contribution to journalArticlepeer-review

88 Scopus citations


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 ofhumanA315TTDP-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-43A315TKi 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-43A315TKi 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.

Original languageEnglish
Pages (from-to)10769-10784
Number of pages16
JournalJournal of Biological Chemistry
Issue number15
StatePublished - 11 Apr 2014


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