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

J Biol Chem. 2014 Apr 11;289(15):10769-10784. doi: 10.1074/jbc.M113.515940. Epub 2014 Feb 10.


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.

Keywords: Amyotrophic Lateral Sclerosis (Lou Gehrig's Disease); Mitochondrial Metabolism; Mouse Genetics; Mutagenesis Site-specific; Neurological Diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Amyotrophic Lateral Sclerosis / genetics
  • Amyotrophic Lateral Sclerosis / metabolism*
  • Animals
  • Behavior, Animal
  • Blood Glucose / metabolism
  • Body Weight
  • CD36 Antigens / metabolism
  • Cholesterol, HDL / metabolism
  • DNA, Complementary / metabolism
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Embryonic Stem Cells / cytology
  • Fatty Acids / metabolism
  • Female
  • Gene Expression Regulation*
  • Gene Knock-In Techniques
  • Genome
  • Genotype
  • Heterozygote
  • Humans
  • Male
  • Maze Learning
  • Mice
  • Mice, Transgenic
  • Mitochondria / pathology*
  • Motor Neurons / metabolism
  • Mutagenesis, Site-Directed
  • Mutation
  • Phenotype
  • Ubiquitin-Protein Ligases / metabolism


  • Blood Glucose
  • CD36 Antigens
  • Cholesterol, HDL
  • DNA, Complementary
  • DNA-Binding Proteins
  • Fatty Acids
  • Ubiquitin-Protein Ligases
  • parkin protein