Neuronal Expression of UBQLN2P497H Exacerbates TDP-43 Pathology in TDP-43G348C Mice through Interaction with Ubiquitin

Mol Neurobiol. 2019 Jul;56(7):4680-4696. doi: 10.1007/s12035-018-1411-3. Epub 2018 Oct 30.


Mutations in the gene encoding ubiquilin-2 (UBQLN2) are linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). UBQLN2 plays a central role in ubiquitin proteasome system (UPS) and UBQLN2 up-regulation exacerbates TDP-43 cytoplasmic aggregates. To analyze interaction between UBQLN2 and TDP-43 and to produce a relevant ALS animal model, we have generated a new transgenic mouse expressing UBQLN2P497H under the neurofilament heavy (NFH) gene promoter. The UBQLN2P497H mice were then bred with our previously described TDP-43G348C mice to generate double-transgenic UBQLN2P497H; TDP-43G348C mice. With low-expression levels of UBQLN2, the double-transgenic mice developed TDP-43 cytosolic accumulations in motor neurons starting at 5 months of age. These double-transgenic mice exhibited motor neuron loss, muscle atrophy, as well as motor and cognitive deficits during aging. The microglia from double-transgenic mice were hyperresponsive to intraperitoneal injection of lipopolysaccharide (LPS). In vivo and in vitro analyses suggested that extra UBQLN2 proteins can exacerbate cytoplasmic TDP-43 accumulations by competing with the UPS for binding to ubiquitin. Thus, increasing the pool of ubiquitin promoted the UPS function with ensuing reduction of TDP-43 cytosolic accumulations. In conclusion, the double-transgenic UBQLN2P497H; TDP-43G348C mice provides a unique mouse model of ALS/FTD with enhanced TDP-43 pathology that can be exploited for drug testing.

Keywords: Amyotrophic lateral sclerosis (ALS); Animal models; Mice; Neuroinflammation; TAR DNA-binding protein 43 (TDP-43); Ubiquilin-2 (UBQLN2); Ubiquitin.

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Adaptor Proteins, Vesicular Transport / metabolism*
  • Animals
  • Autophagy-Related Proteins
  • Axons / pathology
  • Cell Line, Tumor
  • Cognitive Dysfunction / pathology
  • Cytosol / metabolism
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Gliosis / pathology
  • Humans
  • Inflammation / pathology
  • Mice
  • Mice, Mutant Strains
  • Mice, Transgenic
  • Motor Neurons / metabolism
  • Motor Neurons / pathology
  • Mutation / genetics*
  • NF-kappa B / metabolism
  • Neurons / metabolism*
  • Protein Binding
  • Ubiquitin / metabolism*


  • Adaptor Proteins, Signal Transducing
  • Adaptor Proteins, Vesicular Transport
  • Autophagy-Related Proteins
  • DNA-Binding Proteins
  • NF-kappa B
  • TDP-43 protein, mouse
  • UBQLN2 protein, mouse
  • Ubiquitin