Age at symptom onset and death and disease duration in genetic frontotemporal dementia : an international retrospective cohort study

Background: Frontotemporal dementia is a heterogenous neurodegenerative disorder, with about a third of cases being genetic. Most of this genetic component is accounted for by mutations in GRN, MAPT, and C9orf72. In this study, we aimed to complement previous phenotypic studies by doing an international study of age at symptom onset, age at death, and disease duration in individuals with mutations in GRN, MAPT, and C9orf72. Methods: In this international, retrospective cohort study, we collected data on age at symptom onset, age at death, and disease duration for patients with pathogenic mutations in the GRN and MAPT genes and pathological expansions in the C9orf72 gene through the Frontotemporal Dementia Prevention Initiative and from published papers. We used mixed effects models to explore differences in age at onset, age at death, and disease duration between genetic groups and individual mutations. We also assessed correlations between the age at onset and at death of each individual and the age at onset and at death of their parents and the mean age at onset and at death of their family members. Lastly, we used mixed effects models to investigate the extent to which variability in age at onset and at death could be accounted for by family membership and the specific mutation carried. Findings: Data were available from 3403 individuals from 1492 families: 1433 with C9orf72 expansions (755 families), 1179 with GRN mutations (483 families, 130 different mutations), and 791 with MAPT mutations (254 families, 67 different mutations). Mean age at symptom onset and at death was 49\ub75 years (SD 10\ub70; onset) and 58\ub75 years (11\ub73; death) in the MAPT group, 58\ub72 years (9\ub78; onset) and 65\ub73 years (10\ub79; death) in the C9orf72 group, and 61\ub73 years (8\ub78; onset) and 68\ub78 years (9\ub77; death) in the GRN group. Mean disease duration was 6\ub74 years (SD 4\ub79) in the C9orf72 group, 7\ub71 years (3\ub79) in the GRN group, and 9\ub73 years (6\ub74) in the MAPT group. Individual age at onset and at death was significantly correlated with both parental age at onset and at death and with mean family age at onset and at death in all three groups, with a stronger correlation observed in the MAPT group (r=0\ub745 between individual and parental age at onset, r=0\ub763 between individual and mean family age at onset, r=0\ub758 between individual and parental age at death, and r=0\ub769 between individual and mean family age at death) than in either the C9orf72 group (r=0\ub732 individual and parental age at onset, r=0\ub736 individual and mean family age at onset, r=0\ub738 individual and parental age at death, and r=0\ub740 individual and mean family age at death) or the GRN group (r=0\ub722 individual and parental age at onset, r=0\ub718 individual and mean family age at onset, r=0\ub722 individual and parental age at death, and r=0\ub732 individual and mean family age at death). Modelling showed that the variability in age at onset and at death in the MAPT group was explained partly by the specific mutation (48%, 95% CI 35\u201362, for age at onset; 61%, 47\u201373, for age at death), and even more by family membership (66%, 56\u201375, for age at onset; 74%, 65\u201382, for age at death). In the GRN group, only 2% (0\u201310) of the variability of age at onset and 9% (3\u201321) of that of age of death was explained by the specific mutation, whereas 14% (9\u201322) of the variability of age at onset and 20% (12\u201330) of that of age at death was explained by family membership. In the C9orf72 group, family membership explained 17% (11\u201326) of the variability of age at onset and 19% (12\u201329) of that of age at death. Interpretation: Our study showed that age at symptom onset and at death of people with genetic frontotemporal dementia is influenced by genetic group and, particularly for MAPT mutations, by the specific mutation carried and by family membership. Although estimation of age at onset will be an important factor in future pre-symptomatic therapeutic trials for all three genetic groups, our study suggests that data from other members of the family will be particularly helpful only for individuals with MAPT mutations. Further work in identifying both genetic and environmental factors that modify phenotype in all groups will be important to improve such estimates. Funding: UK Medical Research Council, National Institute for Health Research, and Alzheimer's Society

Simvastatin Inducing Pc3 Prostate Cancer Cell Necrosis Mediated By Calcineurin And Mitochondrial Dysfunction

In the present study we analyzed the mechanisms of simvastatin toxicity for the PC3 human prostate cancer cell line. At 10 μM, simvastatin induced principally apoptosis, which was prevented by mevalonic acid but not by cyclosporin A, the inhibitor of calcineurin and mitochondrial permeability transition (MPT). At 60 μM, simvastatin induced the necrosis of PC3 cells insensitive to mevalonic acid. Cell necrosis was preceded by a threefold increase in cytosolic free Ca 2+ concentration and a significant decrease in both respiration rate and mitochondrial membrane potential. Both mitochondrial dysfunction and necrosis were sensitive to the compounds cyclosporin A and bongkrekic acid, as well as the calcineurin inhibitor FK506. We have concluded that simvastatin-induced PC3 cells apoptosis is dependent on 3-hydroxy-3-methylglutaryl coenzyme-A reductase inhibition and independent of MPT, whereas necrosis is dependent on mitochondrial dysfunction caused, at least in part, by calcineurin. © 2008 Springer Science+Business Media, LLC.404307314Almeida, S., Domingues, A., Rodrigues, L., (2004) Neurobiol Dis, 17, pp. 435-444Ankarcrona, M., Dypbukt, J.M., Orrenius, S., (1996) FEBS Lett, 394, pp. 321-324Campos, C.B.L., Degasperi, G.R., Pacífico, D.S., (2004) Biochem Pharmacol, 68, pp. 2197-2206Collins, R., Armitage, J., Parish, S., (2003) Lancet, 361, pp. 2005-2016Dawson, T.M., Steiner, J.P., Dawson, V.L., (1993) Proc Natl Acad Sci U S a, 90, pp. 9808-9812Degasperi, G.R., Velho, J.A., Zecchin, K.G., (2006) J Bioenerg Biomembr, 38, pp. 1-10Demierre, M.-F., Higgins, P.D.R., Gruber, S.B., (2005) Nat Rev Cancer, 5, pp. 930-942Ghosh, P.M., Ghosh-Choudhury, N., Moyer, M.L., (1999) Oncogene, 18, pp. 4120-4130Gunter, K.K., Gunter, T.E., (1994) J Bioenerg Biomembr, 26, pp. 471-485Halestrap, A.P., Brenner, C., (2003) Curr Med Chem, 10, pp. 1507-1525Halestrap, A.P., Connern, C.P., Griffths, E.J., (1997) Mol Cell Biochem, 174, pp. 167-172Hara, M.R., Snyder, S.H., (2007) Toxicol, 47, pp. 117-141Hindler, K., Cleeland, C.S., Rivera, E., (2006) Oncologist, 11, pp. 306-315Holden, M.J., Sze, H., (1989) Plant Physiol, 91, pp. 1296-1302Hoque, A., Chen, H., Xu, X.C., (2008) Cancer Epidemiol Biomarkers Prev, 17, pp. 88-94Kowaltowski, A.J., Castilho, R.F., Vercesi, A.E., (2001) FEBS Lett, 495, pp. 12-15Kroemer, G., Galluzi, L., Brenner, C., (2007) Physiol Rev, 87, pp. 99-163Li, Y.C., Park, M.J., Ye, S.-K., (2006) Am J Pathol, 168, pp. 1107-1118Liu, J., Farmer, J.D.J., Lane, W.S., Friedman, J., (1991) Cell, 66, pp. 807-815Manev, H., Favaron, M., Candeo, P., (1993) Brain Res, 624, pp. 331-335Marcelli, M., Glenn, R.C., Haidacher, S.J., (1998) Cancer Res, 58, pp. 76-83Park, C., Lee, I., Kang, W.K., (2001) Carcinogenesis, 22, pp. 1727-1731Platz, E.A., Leitzmann, M.F., Visvanathan, K., (2006) J Natl Cancer Inst, 98, pp. 1819-1825Rao, S., Porter, D.C., Chen, X., (1999) Proc Natl Acad Sci U S a, 96, pp. 7797-7802Shepherd, J., Cobbe, S.M., Ford, I., (1995) N Engl J Med, 333, pp. 1301-1307Shibasaki, F., McKeon, F., (1995) Cell Biol, 131, pp. 735-743Sivaprasad, U., Abbas, T., Dutta, A., (2006) Mol Cancer Ther, 5, pp. 2310-2316Springer, J.E., Azbill, R.D., Nottingham, S.A., (2000) J Neurosci, 20, pp. 7246-7251Ukomadu, C., Dutta, A., (2003) J Biol Chem, 278, pp. 4840-4846Velho, J.A., Okanobo, H., Degasperi, G.R., (2006) Toxicology, 219, pp. 124-132Vercesi, A.E., Kowaltowski, A.J., Oliveira, H.C.F., (2006) Front Biosc, 11, pp. 2554-2564Wang, H.G., Pathan, N., Ethell, I.M., (1999) Science, 284, pp. 339-343Weitz-Schmidt, G., Welzenbach, K., Brinkmann, V., (2001) Nat Med, 7, pp. 687-692Zecchin, K.G., Seidinger, A.L.O., Degasperi, G.R., (2007) J Bioenerg Biomembr, 39, pp. 186-19

Protection Of Rat Skeletal Muscle Fibers By Either L-carnitine Or Coenzyme Q10 Against Statins Toxicity Mediated By Mitochondrial Reactive Oxygen Generation

Mitochondrial redox imbalance has been implicated in mechanisms of aging, various degenerative diseases and drug-induced toxicity. Statins are safe and well-tolerated therapeutic drugs that occasionally induce myotoxicity such as myopathy and rhabdomyolysis. Previous studies indicate that myotoxicity caused by statins may be linked to impairment of mitochondrial functions. Here, we report that 1-h incubation of permeabilized rat soleus muscle fiber biopsies with increasing concentrations of simvastatin (1-40 μM) slowed the rates of ADP-or FCCP-stimulated respiration supported by glutamate/malate in a dose-dependent manner, but caused no changes in resting respiration rates. Simvastatin (1 μM) also inhibited the ADP-stimulated mitochondrial respiration supported by succinate by 24% but not by TMPD/ascorbate. Compatible with inhibition of respiration, 1 μM simvastatin stimulated lactate release from soleus muscle samples by 26%. Co-incubation of muscle samples with 1 mM L-carnitine, 100 μM mevalonate or 10 μM coenzyme Q10 (Co-Q10) abolished simvastatin effects on both mitochondrial glutamate/malate-supported respiration and lactate release. Simvastatin (1 μM) also caused a 2-fold increase in the rate of hydrogen peroxide generation and a decrease in Co-Q10 content by 44%. Mevalonate, Co-Q10 or L-carnitine protected against stimulation of hydrogen peroxide generation but only mevalonate prevented the decrease in Co-Q10 content. Thus, independently of Co-Q10 levels, L-carnitine prevented the toxic effects of simvastatin. This suggests that mitochondrial respiratory dysfunction induced by simvastatin, is associated with increased generation of superoxide, at the levels of complexes-I and II of the respiratory chain. 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Administration Of A Murine Diet Supplemented With Conjugated Linoleic Acid Increases The Expression And Activity Of Hepatic Uncoupling Proteins

Daily intake of conjugated linoleic acid (CLA) has been shown to reduce body fat accumulation and to increase body metabolism; this latter effect has been often associated with the up-regulation of uncoupling proteins (UCPs). Here we addressed the effects of a CLA-supplemented murine diet (∼2 % CLA mixture, cis-9, trans-10 and trans-10, cis-12 isomers; 45 % of each isomer on alternating days) on mitochondrial energetics, UCP2 expression/activity in the liver and other associated morphological and functional parameters, in C57BL/6 mice. Diet supplementation with CLA reduced both lipid accumulation in adipose tissues and triacylglycerol plasma levels, but did not augment hepatic lipid storage. Livers of mice fed a diet supplemented with CLA showed high UCP2 mRNA levels and the isolated hepatic mitochondria showed indications of UCP activity: in the presence of guanosine diphosphate, the higher stimulation of respiration promoted by linoleic acid in mitochondria from the CLA mice was almost completely reduced to the level of the stimulation from the control mice. Despite the increased generation of reactive oxygen species through oxi-reduction reactions involving NAD+/NADH in the Krebs cycle, no oxidative stress was observed in the liver. In addition, in the absence of free fatty acids, basal respiration rates and the phosphorylating efficiency of mitochondria were preserved. 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Visualizing Inhibition Of Fatty Acid Synthase Through Mass Spectrometric Analysis Of Mitochondria From Melanoma Cells

Fatty acid synthase (FASN) is the metabolic enzyme responsible for the endogenous synthesis of the saturated long-chain fatty acid palmitate. In contrast to most normal cells, FASN is overexpressed in a variety of human cancers including cutaneous melanoma, in which its levels of expression are associated with a poor prognosis and depth of invasion. Recently, we have demonstrated the mitochondrial involvement in FASN inhibition-induced apoptosis in melanoma cells. Herein we compare, via electrospray ionization mass spectrometry (ESI-MS), free fatty acids (FFA) composition of mitochondria isolated from control (EtOH-treated cells) and Orlistat-treated B16-F10 mouse melanoma cells. Principal component analysis (PCA) was applied to the ESI-MS data and found to separate the two groups of samples. Mitochondria from control cells showed predominance of six ions, that is, those of m/z 157 (Pelargonic, 9:0), 255 (Palmitic, 16:0), 281 (Oleic, 18:1), 311 (Arachidic, 20:0), 327 (Docosahexaenoic, 22:6) and 339 (Behenic, 22:0). In contrast, FASN inhibition with Orlistat changes significantly mitochondrial FFA composition by reducing synthesis of palmitic acid, and its elongation and unsaturation products, such as arachidic and behenic acids, and oleic acid, respectively. ESI-MS of mitochondria isolated from Orlistat-treated cells presented therefore three major ions of m/z 157 (Pelargonic, 9:0), 193 (unknown) and 199 (Lauric, 12:0). These findings demonstrate therefore that FASN inhibition by Orlistat induces significant changes in the FFA composition of mitochondria. © 2011 John Wiley & Sons, Ltd.253449452Smith, S., (1994) FASEB J, 8, p. 1248Menendez, J.A., Lupu, R., (2007) Nat. Rev. Cancer, 7, p. 763Weiss, L., Hoffmann, G.E., Schreiber, R., (1986) Biol. Chem. Hoppe Seyler, 367, p. 905Kuhajda, F.P., (2000) Nutrition, 16, p. 202Alo, P.L., Visca, P., Framarino, M.L., (2000) Oncol. Rep., 7, p. 1383Pizer, E.S., Jackisch, C., Wood, F.D., (1996) Cancer Res., 56, p. 2745Pizer, E.S., Wood, F.D., Heine, H.S., (1996) Cancer Res., 56, p. 1189Gansler, T.S., Hardman III, W., Hunt, D.A., (1997) Hum. Pathol., 28, p. 686Dhanasekaran, S.M., Barrette, T.R., Ghosh, D., (2001) Nature, 412, p. 822Swinnen, J.V., Roskams, T., Joniau, S., (2002) Int. J. Cancer, 98, p. 19Innocenzi, D., Alo, P.L., Balzani, A., (2003) J. Cutan. Pathol., 30, p. 23Rossi, S., Graner, E., Febbo, P., (2003) Mol. Cancer Res., 1, p. 707Takahiro, T., Shinichi, K., Toshimitsu, S., (2003) Clin. Cancer Res., 9, p. 2204Visca, P., Sebastiani, V., Botti, C., (2004) Anticancer Res., 24, p. 4169Kapur, P., Rakheja, D., Roy, L.C., (2005) Mod. Pathol., 18, p. 1107Van De Sande, T., Roskams, T., Lerut, E., (2005) J. Pathol., 206, p. 214Rossi, S., Ou, W., Tang, D., (2006) J. Pathol., 209, p. 369Dowling, S., Cox, J., Cenedella, R.J., (2009) Lipids, 44, p. 489Furuya, Y., Akimoto, S., Yasuda, K., (1997) Anticancer Res., 17, p. 4589Pizer, E.S., Chrest, F.J., Digiuseppe, J.A., (1998) Cancer Res., 58, p. 4611Li, J.N., Gorospe, M., Chrest, F.J., (2001) Cancer Res., 61, p. 1493Zhou, W., Han, W.F., Landree, L.E., (2007) Cancer Res., 67, p. 2964Kridel, S.J., Axelrod, F., Rozenkrantz, N., (2004) Cancer Res., 64, p. 2070Carvalho, M.A., Zecchin, K.G., Seguin, F., (2008) Int. J. Cancer, 123, p. 2557Zecchin, K.G., Rossato, F.A., Raposo, H.F., (2010) Lab. Invest., , DOI: 10.1038/labinvest.2010.157Swinnen, J.V., Van Veldhoven, P.P., Timmermans, L., (2003) Biochem. Biophys. Res. Commun., 302, p. 898Catharino, R.R., Haddad, R., Cabrini, L.G., (2005) Anal. Chem., 77, p. 7429Yang, L., Bennett, R., Strum, J., (2009) Anal. Bioanal. Chem., 393, p. 643Fenn, J.B., Mann, M., Meng, C.K., (1989) Science, 246, p. 64Catharino, R.R., Milagre, H.M.S., Saraiva, A.S., (2007) Energy Fuels, 21, p. 3698Ferreira, C.R., Souza, G., Riccio, M.F., (2009) Rapid Commun. Mass Spectrom., 23, p. 1313Santos, L.S., Catharino, R.R., Aguiar, C.L., (2006) J. Radioanal. Nucl. Chem., 269, p. 505Martin, E.B., Morris, A.J., Zhang, J., (1996) IEE Proc. - Control Theory and Applications, 143, p. 132Sumner, L.W., Mendes, P., Dixon, R.A., (2003) Phytochemistry, 62, p. 817Ferreira, C.R., Saraiva, A.S., Catharino, R.R., (2010) J. Lipid Res., , DOI: 10.1194/jlr.D001768Knowles, L.M., Axelrod, F., Browne, C.D., (2004) J. Biol. Chem., 279, p. 30540Abou-Khalil, S., Abou-Khalil, W.H., Planas, L., (1985) Biochem. Biophys. Res. Commun., 127, p. 1039Bligh, E.G., Dyer, W.J., (1959) Can. J. Biochem. Physiol., 37, p. 911Schrauwen, P., Saris, W.H.M., Hesselink, M.K.C., (2001) FASEB J, 15, p. 2497De Freitas, E.R.L., Soares, P.R.O., Santos, R.D., (2008) J. Nanosci. Nanotechnol., 8, p. 2385Liu, J., Shimizu, K., Kondo, R., (2009) Chem. Biodivers., 6, p. 50

Galignani's messenger

25 juillet 18931893/07/25 (N24790)

Mitochondrial Atp-sensitive K+ Channels As Redox Signals To Liver Mitochondria In Response To Hypertriglyceridemia

We have recently demonstrated that hypertriglyceridemic (HTG) mice present both elevated body metabolic rates and mild mitochondrial uncoupling in the liver owing to stimulated activity of the ATP-sensitive potassium channel (mitoKATP). Because lipid excess normally leads to cell redox imbalance, we examined the hepatic oxidative status in this model. Cell redox imbalance was evidenced by increased total levels of carbonylated proteins, malondialdehydes, and GSSG/GSH ratios in HTG livers compared to wild type. In addition, the activities of the extramitochondrial enzymes NADPH oxidase and xanthine oxidase were elevated in HTG livers. In contrast, Mn-superoxide dismutase activity and content, a mitochondrial matrix marker, were significantly decreased in HTG livers. Isolated HTG liver mitochondria presented lower rates of H2O2 production, which were reversed by mitoKATP antagonists. In vivo antioxidant treatment with N-acetylcysteine decreased both mitoKATP activity and metabolic rates in HTG mice. These data indicate that high levels of triglycerides increase reactive oxygen generation by extramitochondrial enzymes that promote mitoKATP activation. The mild uncoupling mediated by mitoKATP increases metabolic rates and protects mitochondria against oxidative damage. Therefore, a biological role for mitoKATP as a redox sensor is shown here for the first time in an in vivo model of systemic and cellular lipid excess. © 2009 Elsevier Inc. 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Inhibition of fatty acid synthase in melanoma cells activates the intrinsic pathway of apoptosis

Fatty acid synthase (FASN) is the metabolic enzyme responsible for the endogenous synthesis of the saturated long-chain fatty acid, palmitate. In contrast to most normal cells, FASN is overexpressed in a variety of human cancers, including cutaneous melanoma, in which its levels of expression are associated with tumor invasion and poor prognosis. We have previously shown that FASN inhibition with orlistat significantly reduces the number of spontaneous mediastinal lymph node metastases following the implantation of B16-F10 mouse melanoma cells in the peritoneal cavity of C57BL/6 mice. In this study, we investigate the biological mechanisms responsible for the FASN inhibition-induced apoptosis in B16-F10 cells. Both FASN inhibitors, cerulenin and orlistat, significantly reduced melanoma cell proliferation and activated the intrinsic pathway of apoptosis, as demonstrated by the cytochrome c release and caspase-9 and-3 activation. Further, apoptosis was preceded by an increase in both reactive oxygen species production and cytosolic calcium concentrations and independent of p53 activation and mitochondrial permeability transition. Taken together, these findings demonstrate the mitochondrial involvement in FASN inhibition-induced apoptosis in melanoma cells.912232240CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQCOORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIOR - CAPESFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP470539/2008-9Sem informação08/57471-7; 07/54639-

Inhibition Of Fatty Acid Synthase In Melanoma Cells Activates The Intrinsic Pathway Of Apoptosis

Fatty acid synthase (FASN) is the metabolic enzyme responsible for the endogenous synthesis of the saturated long-chain fatty acid, palmitate. In contrast to most normal cells, FASN is overexpressed in a variety of human cancers, including cutaneous melanoma, in which its levels of expression are associated with tumor invasion and poor prognosis. We have previously shown that FASN inhibition with orlistat significantly reduces the number of spontaneous mediastinal lymph node metastases following the implantation of B16-F10 mouse melanoma cells in the peritoneal cavity of C57BL/6 mice. In this study, we investigate the biological mechanisms responsible for the FASN inhibition-induced apoptosis in B16-F10 cells. Both FASN inhibitors, cerulenin and orlistat, significantly reduced melanoma cell proliferation and activated the intrinsic pathway of apoptosis, as demonstrated by the cytochrome c release and caspase-9 and-3 activation. Further, apoptosis was preceded by an increase in both reactive oxygen species production and cytosolic calcium concentrations and independent of p53 activation and mitochondrial permeability transition. Taken together, these findings demonstrate the mitochondrial involvement in FASN inhibition-induced apoptosis in melanoma cells. © 2011 USCAP, Inc All rights reserved.912232240Smith, S., The animal fatty acid synthase: One gene, one polypeptide, seven enzymes (1994) FASEB J, 8, pp. 1248-1259Menendez, J.A., Lupu, R., Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis (2007) Nat Rev Cancer, 7, pp. 763-777Brink, J., Ludtke, S.J., Yang, C.Y., Quaternary structure of human fatty acid synthase by electron cryomicroscopy (2002) Proc Natl Acad Sci USA, 99, pp. 138-143Weiss, L., Hoffmann, G.E., Schreiber, R., Fatty-acid biosynthesis in man, a pathway of minor importance. 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