Inducible transgenic expression of tripeptidyl peptidase 1 in a mouse model of late-infantile neuronal ceroid lipofuscinosis

PLoS One. 2018 Feb 6;13(2):e0192286. doi: 10.1371/journal.pone.0192286. eCollection 2018.


Late-infantile neuronal ceroid lipofuscinosis is a fatal neurodegenerative disease of children caused by mutations resulting in loss of activity of the lysosomal protease, tripeptidyl peptidase 1 (TPP1). While Tpp1-targeted mouse models of LINCL exist, the goal of this study was to create a transgenic mouse with inducible TPP1 to benchmark treatment approaches, evaluate efficacy of treatment at different stages of disease, and to provide insights into the pathobiology of disease. A construct containing a loxP-flanked stop cassette inserted between the chicken-actin promoter and a sequence encoding murine TPP1 (TgLSL-TPP1) was integrated into the ROSA26 locus in mice by homologous recombination. Tested in both transfected CHO cells and in transgenic mice, the TgLSL-TPP1 did not express TPP1 until cre-mediated removal of the LSL cassette, which resulted in supraphysiological levels of TPP1 activity. We tested four cre/ERT2 transgenes to allow tamoxifen-inducible removal of the LSL cassette and subsequent TPP1 expression at any stage of disease. However, two of the cre/ERT2 driver transgenes had significant cre activity in the absence of tamoxifen, while cre-mediated recombination could not be induced by tamoxifen by two others. These results highlight potential problems with the use of cre/ERT2 transgenes in applications that are sensitive to low levels of basal cre expression. However, the germline-recombined mouse transgenic that constitutively overexpresses TPP1 will allow long-term evaluation of overexposure to the enzyme and in cell culture, the inducible transgene may be a useful tool in biomarker discovery projects.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aminopeptidases / genetics*
  • Animals
  • CHO Cells
  • Cricetulus
  • Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / genetics*
  • Disease Models, Animal*
  • Gene Expression Regulation, Enzymologic / drug effects
  • Mice
  • Mice, Transgenic
  • Neuronal Ceroid-Lipofuscinoses / enzymology*
  • Neuronal Ceroid-Lipofuscinoses / genetics
  • Serine Proteases / genetics*
  • Tamoxifen / pharmacology
  • Transgenes
  • Tripeptidyl-Peptidase 1


  • Tpp1 protein, mouse
  • Tripeptidyl-Peptidase 1
  • Tamoxifen
  • Serine Proteases
  • Aminopeptidases
  • Dipeptidyl-Peptidases and Tripeptidyl-Peptidases