Novel telomerase-increasing compound in mouse brain delays the onset of amyotrophic lateral sclerosis.

EMBO Molecular Medicine
E EitanE Priel

Abstract

Telomerase is expressed in the neonatal brain, in distinct regions of adult brain, and was shown to protect developing neurons from apoptosis. Telomerase reactivation by gene manipulation reverses neurodegeneration in aged telomerase-deficient mice. Hence, we and others hypothesized that increasing telomerase expression by pharmaceutical compounds may protect brain cells from death caused by damaging agents. In this study, we demonstrate for the first time that the novel compound AGS-499 increases telomerase activity and expression in the mouse brain and spinal cord (SC). It exerts neuroprotective effects in NMDA-injected CD-1 mice, delays the onset and progression of the amyotrophic lateral sclerosis (ALS) disease in SOD1 transgenic mice, and, after the onset of ALS, it increases the survival of motor neurons in the SC by 60%. The survival of telomerase-expressing cells (i.e. motor neurons), but not telomerase-deficient cells, exposed to oxidative stress was increased by AGS-499 treatment, suggesting that the AGS-499 effects are telomerase-mediated. Therefore, a controlled and transient increase in telomerase expression and activity in the brain by AGS-499 may exert neuroprotective effects.

References

Dec 1, 1989·Proceedings of the National Academy of Sciences of the United States of America·J J FeigenbaumM Sokolovsky
Jan 1, 1980·Annual Review of Genetics·T ManiatisR M Lawn
Jan 1, 1994·Cold Spring Harbor Symposia on Quantitative Biology·C B HarleyC W Greider
Sep 2, 1998·Proceedings of the National Academy of Sciences of the United States of America·L Martín-RiveraM A Blasco
Apr 25, 2001·Journal of Neuroscience Research·W KlapperM P Mattson
Sep 26, 2001·The Journal of Biological Chemistry·S BurmaD J Chen
Mar 21, 2002·Proceedings of the National Academy of Sciences of the United States of America·Yie LiuLea Harrington
Aug 29, 2002·Nature Cell Biology·Judy M Y WongKathleen Collins
Dec 31, 2002·Experimental Neurology·Weiming FuMark P Mattson
Jul 8, 2003·Methods in Molecular Biology·S H Kaufmann, P A Svingen
Aug 23, 2003·Molecular and Cellular Neurosciences·Gregg L CaporasoMoses V Chao
Oct 10, 2003·Brain : a Journal of Neurology·P Andreas JonssonStefan L Marklund
Feb 13, 2004·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Hyo Jung KangHan-Woong Lee
May 15, 2004·Journal of Anti-aging Medicine·Barry E Flanary, Wolfgang J Streit
May 26, 2004·Neuroscience Letters·Sunkyung BaekHocheol Kim
Jun 26, 2004·Annual Review of Neuroscience·Lucie I BruijnDon W Cleveland
Jun 2, 2005·Proceedings of the National Academy of Sciences of the United States of America·Kenkichi MasutomiWilliam C Hahn
Jun 25, 2005·Current Molecular Medicine·Calvin B Harley
Sep 22, 2005·Journal of Neuroscience Research·Barry E Flanary, Wolfgang J Streit
Dec 7, 2005·Brain : a Journal of Neurology·P Andreas JonssonStefan L Marklund
Feb 10, 2006·The EMBO Journal·Alex BraimanLawrence E Samelson
Jun 3, 2006·Science·Séverine BoilléeDon W Cleveland
Jul 29, 2006·Biochimica Et Biophysica Acta·Mamatha S NayakDouglas A Kerr
Oct 4, 2006·Neuron·Séverine BoilléeDon W Cleveland
Nov 23, 2006·Antioxidants & Redox Signaling·Ari Barzilai
Dec 6, 2006·Journal of Neuropathology and Experimental Neurology·P Andreas JonssonStefan L Marklund
Aug 24, 2007·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Laura FerraiuoloPamela J Shaw
Sep 28, 2007·Journal of Neuroscience Research·Dusan MatusicaRobert A Rush
Oct 26, 2007·Cell and Tissue Research·Stefan Zimmermann, Uwe M Martens
Nov 8, 2007·Nucleic Acids Research·João F PassosThomas von Zglinicki
Nov 30, 2007·Clinical Interventions in Aging·Yira BermudezPatricia A Kruk
Feb 12, 2008·Blood·Peter M Lansdorp
Feb 15, 2008·Amyotrophic Lateral Sclerosis : Official Publication of the World Federation of Neurology Research Group on Motor Neuron Diseases·Sean ScottJames A Heywood

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Citations

Jul 24, 2013·Trends in Genetics : TIG·Bruno Bernardes de Jesus, Maria A Blasco
Jun 15, 2013·Beilstein Journal of Organic Chemistry·Allison S LimpertNicholas D P Cosford
Feb 25, 2014·Ageing Research Reviews·Virginia Boccardi, Giuseppe Paolisso
Apr 5, 2014·Trends in Neurosciences·Erez EitanMark P Mattson
Aug 22, 2014·Journal of Human Genetics·Bruna De FeliceElio Biffali
Dec 1, 2015·Ageing Research Reviews·Jingwen ZhangGautam Sethi
Apr 22, 2015·Ageing Research Reviews·Virginia BoccardiPatrizia Mecocci
Mar 26, 2013·Biochimica Et Biophysica Acta·Philip McGoldrickLinda Greensmith
Oct 23, 2012·Current Opinion in Cell Biology·Bruno Bernardes de Jesus, Maria A Blasco
Feb 21, 2013·Neurochemistry International·Joshua A SmithNaren L Banik
Jun 21, 2016·Genes·Abbas IshaqGabriele Saretzki
Jul 11, 2016·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Karima Ait-AissaAndreas M Beyer
Jul 28, 2016·Genes·Kathrin Jäger, Michael Walter
May 26, 2018·Arteriosclerosis, Thrombosis, and Vascular Biology·Andreas M Beyer, Laura E Norwood Toro
Dec 25, 2015·Circulation Research·Andreas M BeyerDavid D Gutterman
Feb 4, 2016·Circulation Research·David D GuttermanAndreas M Beyer
Apr 28, 2017·European Respiratory Review : an Official Journal of the European Respiratory Society·Raphael BorieBruno Crestani
Jan 24, 2015·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·John RamunasHelen M Blau
Sep 3, 2020·Molecular Biology Reports·M LulkiewiczB Rubis
Oct 2, 2020·Molecular and Cellular Biochemistry·P Prieto-Oliveira
Jun 6, 2018·Frontiers in Molecular Neuroscience·Meng-Ying LiuQi-Gang Zhou
Nov 19, 2018·Molecular Biology Reports·Aleksandra RomaniukBłażej Rubiś
May 1, 2018·Current Opinion in Obstetrics & Gynecology·Elisa VarelaJuan A García-Velasco
May 5, 2017·Neural Regeneration Research·Satomi Miwa, Gabriele Saretzki
Sep 24, 2019·Current Aging Science·Joan Smith-Sonneborn
Mar 16, 2016·Aging·Birgit LinkusKarin M Danzer
Dec 10, 2019·Biochimica Et Biophysica Acta. Molecular Basis of Disease·Manuel Ros, José María Carrascosa
Jul 17, 2020·International Journal of Biological Macromolecules·Jiequan WangXinhua Liu

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Methods Mentioned

BETA
electrophoresis
PCR
transfection
protein assay
X
ray

Software Mentioned

MAS
Affymetrix
OriginPro7
EZquant

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