title: Disruption of adaptive energy metabolism and elevated ribosomal p-S6K1 levels contribute to INCL pathogenesis: partial rescue by resveratrol.
abstract: The infantile neuronal ceroid lipofuscinosis (INCL) is a devastating neurodegenerative lysosomal storage disease. Despite our knowledge that palmitoyl-protein thioesterase-1 (PPT1)-deficiency causes INCL, the molecular mechanism(s) of neurodegeneration and the drastically reduced lifespan of these patients remain poorly understood. Consequently, an effective treatment for this disease is currently unavailable. We previously reported that oxidative stress-mediated abnormality in mitochondria activates caspases-9 pathway of apoptosis in INCL fibroblasts and in neurons of Ppt1-knockout (Ppt1-KO) mice, which mimic INCL. Since mitochondria play critical roles in maintaining cellular energy homeostasis, we hypothesized that oxidative stress-mediated disruption of energy metabolism and homeostasis may contribute to INCL pathogenesis. We report here that, in cultured INCL fibroblasts and in the brain tissues of Ppt1-KO mice, the NAD(+)/NADH ratio, the levels of phosphorylated-AMPK (p-AMPK), peroxisome proliferator-activated receptor-γ (PPARγ) coactivator-1α (PGC-1α) and Silent Information Regulator T1 (SIRT1) are markedly down-regulated. This suggested an abnormality in AMPK/SIRT1/PGC-1α signaling pathway of energy metabolism. Moreover, we found that, in INCL fibroblasts and in the Ppt1-KO mice, phosphorylated-S6K-1 (p-S6K1) levels, which inversely correlate with lifespan, are markedly elevated. Most importantly, resveratrol (RSV), an antioxidant polyphenol, elevated the NAD(+)/NADH ratio, levels of ATP, p-AMPK, PGC-1α and SIRT1 while decreasing the level of p-S6K1 in both INCL fibroblasts and in Ppt1-KO mice, which showed a modest increase in lifespan. Our results show that disruption of adaptive energy metabolism and increased levels of p-S6K1 are contributing factors in INCL pathogenesis and provide the proof of principle that small molecules such as RSV, which alleviate these abnormalities, may have therapeutic potential.
authors.affiliation: Section on Developmental Genetics, Program on Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892-1830, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Wei
authors.forename: Zhongjian
authors.initials: Z
authors.lastname: Zhang
authors.forename: Arjun
authors.initials: A
authors.lastname: Saha
authors.forename: Shiyong
authors.initials: S
authors.lastname: Peng
authors.forename: Goutam
authors.initials: G
authors.lastname: Chandra
authors.forename: Zenaide
authors.initials: Z
authors.lastname: Quezado
authors.forename: Anil B
authors.initials: AB
authors.lastname: Mukherjee
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004734:Energy Metabolism; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009243:NAD / Q000378:metabolism; D009472:Neuronal Ceroid-Lipofuscinoses / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D018384:Oxidative Stress; D010766:Phosphorylation; D000077185:Resveratrol; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000235:genetics / Q000378:metabolism*; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000235:genetics / Q000378:metabolism*; D012270:Ribosomes / Q000378:metabolism*; D013267:Stilbenes / Q000627:therapeutic use*; D013869:Thiolester Hydrolases / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D013267:Stilbenes; D009243:NAD; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C512964:Rps6ka1 protein, mouse; C448901:ribosomal protein S6 kinase, 70kD, polypeptide 1; D013869:Thiolester Hydrolases; C095299:palmitoyl-protein thioesterase; D000077185:Resveratrol