Genetic modulation of apoptotic pathways fails to alter disease course in tripeptidyl-peptidase 1 deficient mice

Abstract

Late-infantile neuronal ceroid lipofuscinosis (LINCL) is a fatal, incurable neurodegenerative disease of children caused by the loss of the lysosomal protein tripeptidyl-peptidase 1 (TPP1). Previous studies have suggested that Bcl-2-dependent apoptotic pathways are involved in neuronal cell death in LINCL patients and, as a result, anti-apoptotic treatments that increase Bcl-2 activity have been proposed as a potential therapeutic approach. In this study, we have directly investigated whether targeting anti-apoptotic pathways may be of value in LINCL in a mouse model of this disease that lacks TPP1 and which recapitulates many aspect of the human disease, including a greatly shortened life-span. Our approach was to genetically modify apoptotic pathways and determine the effects of these changes on the severe neurodegenerative phenotype of the LINCL mouse. LINCL mice were generated that either lacked the pro-apoptotic p53 or had increased levels of anti-apoptotic Bcl-2, changes that would exacerbate or ameliorate neuronal death, respectively, should pathways involving these proteins be important. Neither modification affected the shortened life-span of the LINCL mouse. These results suggest that either neuronal death in LINCL does not occur via apoptosis or that it occurs via apoptotic pathways not involving p53 or Bcl-2. Alternatively, pathways involving p53 and/or Bcl-2 may be involved in neuronal death under normal circumstances but may not be the only routes to this end. Importantly, our findings suggest that targeting pathways of cell death involving p53 or Bcl-2 do not represent useful directions for developing effective treatment.

Figure 1

Genotyping of mouse models used in this study.

Figure 2

Survival of Tpp1^−/− mice with modified expression of p53 (Panel A) or Bcl-2 (Panel B). Log-rank test of the survival of Tpp1^−/− mice that are p53^−/− and Tg(NSE-bcl-2)⁺ were not significantly different from their respective Tpp1^−/− controls (P values are 0.9280 and 0.6335, respectively). The median survival and number of animals in each group were as follows: Panel A: p53^+/+, 132 days, n=22; p53^+/−, 132 days, n=56; p53^−/−; 131 days, n=19. Panel B: Tg(NSE-bcl-2)⁻, 141 days, n=70; Tg(NSE-bcl-2)⁺,141 days, n=62.