Research Article
The Neuroprotective Role of TERT Influences the Expression of SOD1 in Motor Neurons and Mouse Brain: Implications for fALS
Ailone Tichon, Erez Eitan, Sylvia Tsory, Elie Beit-Yanai and Esther Priel*
Published: 14 October, 2023 | Volume 7 - Issue 2 | Pages: 113-125
Amyotrophic lateral sclerosis (ALS) disease is characterized by degeneration of motor neurons and elevation of brain oxidative stress. Previous studies demonstrated the neuroprotective effects of Telomerase reverse transcriptase (TERT) from oxidative stress. We showed that increasing TERT expression in the brain of the Tg hSOD1G93A mouse ALS model attenuated the disease pathology and increased the survival of motor neurons exposed to oxidative stress. How TERT increased the survival of motor neurons exposed to oxidative stress is not yet clear. Here we investigated the consequence of TERT depletion in motor neuron cells under normal and oxidative stress conditions and in mouse brains of TERT knockout mice, on the expression and activity of SOD1 and catalase enzymes. Depletion of mouse TERT caused mitochondrial dysfunction and impaired catalase and SOD1 activity. Compensation with hTERT restored the activity of SOD1. SOD1 expression increased in the brain of TERT KO and in ALS mice and decreased in the brain of WT mice treated with telomerase-increasing compounds. We suggest that the ability of TERT to protect neurons from oxidative stress affects the expression and activity of SOD1, in a TERT-dependent manner, and supports the notion of TERT as a therapeutic target for neurodegenerative diseases like ALS.
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DOI: 10.29328/journal.jnnd.1001085
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Keywords:
Telomerase, H2O2; Mitochondria; Catalase; SOD1; TERT; TERT KO mice
References
- Mead RJ, Shan N, Reiser HJ, Marshall F, Shaw PJ. Amyotrophic lateral sclerosis: a neurodegenerative disorder poised for successful therapeutic translation. Nat Rev Drug Discov. 2023 Mar;22(3):185-212. doi: 10.1038/s41573-022-00612-2. Epub 2022 Dec 21. PMID: 36543887; PMCID: PMC9768794.
- Andrus PK, Fleck TJ, Gurney ME, Hall ED. Protein oxidative damage in a transgenic mouse model of familial amyotrophic lateral sclerosis. J Neurochem. 1998 Nov;71(5):2041-8. doi: 10.1046/j.1471-4159.1998.71052041.x. PMID: 9798929.
- Ferrante RJ, Browne SE, Shinobu LA, Bowling AC, Baik MJ, MacGarvey U, Kowall NW, Brown RH Jr, Beal MF. Evidence of increased oxidative damage in both sporadic and familial amyotrophic lateral sclerosis. J Neurochem. 1997 Nov;69(5):2064-74. doi: 10.1046/j.1471-4159.1997.69052064.x. PMID: 9349552.
- Boillée S, Vande Velde C, Cleveland DW. ALS: a disease of motor neurons and their nonneuronal neighbors. Neuron. 2006 Oct 5;52(1):39-59. doi: 10.1016/j.neuron.2006.09.018. PMID: 17015226.
- Barber SC, Shaw PJ. Oxidative stress in ALS: key role in motor neuron injury and therapeutic target. Free Radic Biol Med. 2010 Mar 1;48(5):629-41. doi: 10.1016/j.freeradbiomed.2009.11.018. Epub 2009 Dec 4. PMID: 19969067.
- Bendotti C, Carrì MT. Lessons from models of SOD1-linked familial ALS. Trends Mol Med. 2004 Aug;10(8):393-400. doi: 10.1016/j.molmed.2004.06.009. PMID: 15310460.
- De Vos KJ, Grierson AJ, Ackerley S, Miller CC. Role of axonal transport in neurodegenerative diseases. Annu Rev Neurosci. 2008;31:151-73. doi: 10.1146/annurev.neuro.31.061307.090711. PMID: 18558852.
- Peggion C, Scalcon V, Massimino ML, Nies K, Lopreiato R, Rigobello MP, Bertoli A. SOD1 in ALS: Taking Stock in Pathogenic Mechanisms and the Role of Glial and Muscle Cells. Antioxidants (Basel). 2022 Mar 23;11(4):614. doi: 10.3390/antiox11040614. PMID: 35453299; PMCID: PMC9032988.
- De Felice B, Annunziata A, Fiorentino G, Manfellotto F, D'Alessandro R, Marino R, Borra M, Biffali E. Telomerase expression in amyotrophic lateral sclerosis (ALS) patients. J Hum Genet. 2014 Oct;59(10):555-61. doi: 10.1038/jhg.2014.72. Epub 2014 Aug 21. PMID: 25142509.
- Cohen SB, Graham ME, Lovrecz GO, Bache N, Robinson PJ, Reddel RR. Protein composition of catalytically active human telomerase from immortal cells. Science. 2007 Mar 30;315(5820):1850-3. doi: 10.1126/science.1138596. PMID: 17395830.
- Hockemeyer D, Collins K. Control of telomerase action at human telomeres. Nat Struct Mol Biol. 2015 Nov;22(11):848-52. doi: 10.1038/nsmb.3083. PMID: 26581518; PMCID: PMC4765361.
- Park JI, Venteicher AS, Hong JY, Choi J, Jun S, Shkreli M, Chang W, Meng Z, Cheung P, Ji H, McLaughlin M, Veenstra TD, Nusse R, McCrea PD, Artandi SE. Telomerase modulates Wnt signalling by association with target gene chromatin. Nature. 2009 Jul 2;460(7251):66-72. doi: 10.1038/nature08137. PMID: 19571879; PMCID: PMC4349391.
- Daniel M, Peek GW, Tollefsbol TO. Regulation of the human catalytic subunit of telomerase (hTERT). Gene. 2012 May 1;498(2):135-46. doi: 10.1016/j.gene.2012.01.095. Epub 2012 Feb 13. PMID: 22381618; PMCID: PMC3312932.
- Eitan E, Tichon A, Daniel G, Priel E. Telomerase expression in adult and old mouse Purkinje neurons. Rejuvenation Res. 2012 Apr;15(2):206-9. doi: 10.1089/rej.2011.1285. PMID: 22533433.
- Tichon A, Gowda BK, Slavin S, Gazit A, Priel E. Telomerase activity and expression in adult human mesenchymal stem cells derived from amyotrophic lateral sclerosis individuals. Cytotherapy. 2009;11(7):837-48. doi: 10.3109/14653240903136979. PMID: 19903097.
- Liu J, Baykal A, Fung KM, Thompson-Lanza JA, Hoque A, Lippman SM, Sahin A. Human telomerase reverse transcriptase mRNA is highly expressed in normal breast tissues and down-regulated in ductal carcinoma in situ. Int J Oncol. 2004 Apr;24(4):879-84. PMID: 15010825.
- Yasumoto S, Kunimura C, Kikuchi K, Tahara H, Ohji H, Yamamoto H, Ide T, Utakoji T. Telomerase activity in normal human epithelial cells. Oncogene. 1996 Jul 18;13(2):433-9. PMID: 8710384.
- Masutomi K, Yu EY, Khurts S, Ben-Porath I, Currier JL, Metz GB, Brooks MW, Kaneko S, Murakami S, DeCaprio JA, Weinberg RA, Stewart SA, Hahn WC. Telomerase maintains telomere structure in normal human cells. Cell. 2003 Jul 25;114(2):241-53. doi: 10.1016/s0092-8674(03)00550-6. PMID: 12887925.
- Baruch-Eliyahu N, Rud V, Braiman A, Priel E. Telomerase increasing compound protects hippocampal neurons from amyloid beta toxicity by enhancing the expression of neurotrophins and plasticity related genes. Sci Rep. 2019 Dec 2;9(1):18118. doi: 10.1038/s41598-019-54741-7. PMID: 31792359; PMCID: PMC6889131.
- Ding X, Liu X, Wang F, Wang F, Geng X. Role of Senescence and Neuroprotective Effects of Telomerase in Neurodegenerative Diseases. Rejuvenation Res. 2020 Apr;23(2):150-158. doi: 10.1089/rej.2018.2115. Epub 2019 Jul 18. PMID: 31170886.
- Eitan E, Tichon A, Gazit A, Gitler D, Slavin S, Priel E. Novel telomerase-increasing compound in mouse brain delays the onset of amyotrophic lateral sclerosis. EMBO Mol Med. 2012 Apr;4(4):313-29. doi: 10.1002/emmm.201200212. Epub 2012 Feb 20. PMID: 22351600; PMCID: PMC3376858.
- Wan T, Weir EJ, Johnson M, Korolchuk VI, Saretzki GC. Increased telomerase improves motor function and alpha-synuclein pathology in a transgenic mouse model of Parkinson's disease associated with enhanced autophagy. Prog Neurobiol. 2021 Apr;199:101953. doi: 10.1016/j.pneurobio.2020.101953. Epub 2020 Nov 11. PMID: 33188884; PMCID: PMC7938226.
- Yu X, Liu MM, Zheng CY, Liu YT, Wang Z, Wang ZY. Telomerase reverse transcriptase and neurodegenerative diseases. Front Immunol. 2023 Mar 29;14:1165632. doi: 10.3389/fimmu.2023.1165632. PMID: 37063844; PMCID: PMC10091515.
- Ahmed S, Passos JF, Birket MJ, Beckmann T, Brings S, Peters H, Birch-Machin MA, von Zglinicki T, Saretzki G. Telomerase does not counteract telomere shortening but protects mitochondrial function under oxidative stress. J Cell Sci. 2008 Apr 1;121(Pt 7):1046-53. doi: 10.1242/jcs.019372. Epub 2008 Mar 11. PMID: 18334557.
- Haendeler J, Dröse S, Büchner N, Jakob S, Altschmied J, Goy C, Spyridopoulos I, Zeiher AM, Brandt U, Dimmeler S. Mitochondrial telomerase reverse transcriptase binds to and protects mitochondrial DNA and function from damage. Arterioscler Thromb Vasc Biol. 2009 Jun;29(6):929-35. doi: 10.1161/ATVBAHA.109.185546. Epub 2009 Mar 5. PMID: 19265030.
- Choi J, Southworth LK, Sarin KY, Venteicher AS, Ma W, Chang W, Cheung P, Jun S, Artandi MK, Shah N, Kim SK, Artandi SE. TERT promotes epithelial proliferation through transcriptional control of a Myc- and Wnt-related developmental program. PLoS Genet. 2008 Jan;4(1):e10. doi: 10.1371/journal.pgen.0040010. Epub 2007 Dec 13. PMID: 18208333; PMCID: PMC2211538.
- Martens A, Schmid B, Akintola O, Saretzki G. Telomerase Does Not Improve DNA Repair in Mitochondria upon Stress but Increases MnSOD Protein under Serum-Free Conditions. Int J Mol Sci. 2019 Dec 19;21(1):27. doi: 10.3390/ijms21010027. PMID: 31861522; PMCID: PMC6981674.
- Matusica D, Fenech MP, Rogers ML, Rush RA. Characterization and use of the NSC-34 cell line for study of neurotrophin receptor trafficking. J Neurosci Res. 2008 Feb 15;86(3):553-65. doi: 10.1002/jnr.21507. PMID: 17896795.
- Regev L, Ezrielev E, Gershon E, Gil S, Chen A. Genetic approach for intracerebroventricular delivery. Proc Natl Acad Sci U S A. 2010 Mar 2;107(9):4424-9. doi: 10.1073/pnas.0907059107. Epub 2010 Feb 8. PMID: 20142482; PMCID: PMC2840118.
- Kim NW, Piatyszek MA, Prowse KR, Harley CB, West MD, Ho PL, Coviello GM, Wright WE, Weinrich SL, Shay JW. Specific association of human telomerase activity with immortal cells and cancer. Science. 1994 Dec 23;266(5193):2011-5. doi: 10.1126/science.7605428. PMID: 7605428.
- Gething MJ, McCammon K, Sambrook J. Protein folding and intracellular transport: evaluation of conformational changes in nascent exocytotic proteins. Methods Cell Biol. 1989;32:185-206. doi: 10.1016/s0091-679x(08)61171-1. PMID: 2691850.
- Kaufmann SH, Svingen PA. Immunoblot analysis and band depletion assays. Methods Mol Biol. 1999;94:253-68. doi: 10.1385/1-59259-259-7:253. PMID: 12844881.
- Aranda A, Sequedo L, Tolosa L, Quintas G, Burello E, Castell JV, Gombau L. Dichloro-dihydro-fluorescein diacetate (DCFH-DA) assay: a quantitative method for oxidative stress assessment of nanoparticle-treated cells. Toxicol In Vitro. 2013 Mar;27(2):954-63. doi: 10.1016/j.tiv.2013.01.016. Epub 2013 Jan 26. PMID: 23357416.
- Eruslanov E, Kusmartsev S. Identification of ROS using oxidized DCFDA and flow-cytometry. Methods Mol Biol. 2010;594:57-72. doi: 10.1007/978-1-60761-411-1_4. PMID: 20072909.
- Joshi DC, Bakowska JC. Determination of mitochondrial membrane potential and reactive oxygen species in live rat cortical neurons. J Vis Exp. 2011 May 23;(51):2704. doi: 10.3791/2704. PMID: 21654619; PMCID: PMC3143685.
- Tichon A, Eitan E, Kurkalli BG, Braiman A, Gazit A, Slavin S, Beith-Yannai E, Priel E. Oxidative stress protection by novel telomerase activators in mesenchymal stem cells derived from healthy and diseased individuals. Curr Mol Med. 2013 Jul;13(6):1010-22. doi: 10.2174/1566524011313060013. PMID: 23590815.
- Muir JK, Tynan M, Caldwell R, Ellis EF. Superoxide dismutase improves posttraumatic cortical blood flow in rats. J Neurotrauma. 1995 Apr;12(2):179-88. doi: 10.1089/neu.1995.12.179. PMID: 7629864.
- Tada-Oikawa S, Oikawa S, Kawanishi M, Yamada M, Kawanishi S. Generation of hydrogen peroxide precedes loss of mitochondrial membrane potential during DNA alkylation-induced apoptosis. FEBS Lett. 1999 Jan 8;442(1):65-9. doi: 10.1016/s0014-5793(98)01618-4. PMID: 9923606.
- González-Giraldo Y, Forero DA, Echeverria V, Gonzalez J, Ávila-Rodriguez M, Garcia-Segura LM, Barreto GE. Neuroprotective effects of the catalytic subunit of telomerase: A potential therapeutic target in the central nervous system. Ageing Res Rev. 2016 Jul;28:37-45. doi: 10.1016/j.arr.2016.04.004. Epub 2016 Apr 16. PMID: 27095058.
- Petersen S, Saretzki G, von Zglinicki T. Preferential accumulation of single-stranded regions in telomeres of human fibroblasts. Exp Cell Res. 1998 Feb 25;239(1):152-60. doi: 10.1006/excr.1997.3893. PMID: 9511733.
- Gordon DM, Santos JH. The emerging role of telomerase reverse transcriptase in mitochondrial DNA metabolism. J Nucleic Acids. 2010 Sep 21;2010:390791. doi: 10.4061/2010/390791. PMID: 20936168; PMCID: PMC2945669.
- Massard C, Zermati Y, Pauleau AL, Larochette N, Métivier D, Sabatier L, Kroemer G, Soria JC. hTERT: a novel endogenous inhibitor of the mitochondrial cell death pathway. Oncogene. 2006 Aug 3;25(33):4505-14. doi: 10.1038/sj.onc.1209487. Epub 2006 Apr 17. Erratum in: Oncogene. 2013 Jan 24;32(4):536. PMID: 16619047.
- Saretzki G. Telomerase, mitochondria and oxidative stress. Exp Gerontol. 2009 Aug;44(8):485-92. doi: 10.1016/j.exger.2009.05.004. Epub 2009 May 18. PMID: 19457450.
- Brand MD, Nicholls DG. Assessing mitochondrial dysfunction in cells. Biochem J. 2011 Apr 15;435(2):297-312. doi: 10.1042/BJ20110162. Erratum in: Biochem J. 2011 Aug 1;437(3):575. PMID: 21726199; PMCID: PMC3076726.
- Yoon YG, Haug CL, Koob MD. Interspecies mitochondrial fusion between mouse and human mitochondria is rapid and efficient. Mitochondrion. 2007 May;7(3):223-9. doi: 10.1016/j.mito.2006.11.022. Epub 2006 Dec 9. PMID: 17251069; PMCID: PMC2693707.
- Godon C, Lagniel G, Lee J, Buhler JM, Kieffer S, Perrot M, Boucherie H, Toledano MB, Labarre J. The H2O2 stimulon in Saccharomyces cerevisiae. J Biol Chem. 1998 Aug 28;273(35):22480-9. doi: 10.1074/jbc.273.35.22480. PMID: 9712873.
- Lee J, Godon C, Lagniel G, Spector D, Garin J, Labarre J, Toledano MB. Yap1 and Skn7 control two specialized oxidative stress response regulons in yeast. J Biol Chem. 1999 Jun 4;274(23):16040-6. doi: 10.1074/jbc.274.23.16040. PMID: 10347154.
- Martins D, English AM. Catalase activity is stimulated by H(2)O(2) in rich culture medium and is required for H(2)O(2) resistance and adaptation in yeast. Redox Biol. 2014 Jan 10;2:308-13. doi: 10.1016/j.redox.2013.12.019. PMID: 24563848; PMCID: PMC3926110.
- Ebert R, Ulmer M, Zeck S, Meissner-Weigl J, Schneider D, Stopper H, Schupp N, Kassem M, Jakob F. Selenium supplementation restores the antioxidative capacity and prevents cell damage in bone marrow stromal cells in vitro. Stem Cells. 2006 May;24(5):1226-35. doi: 10.1634/stemcells.2005-0117. Epub 2006 Jan 19. PMID: 16424399.
- Berdyński M, Miszta P, Safranow K, Andersen PM, Morita M, Filipek S, Żekanowski C, Kuźma-Kozakiewicz M. SOD1 mutations associated with amyotrophic lateral sclerosis analysis of variant severity. Sci Rep. 2022 Jan 7;12(1):103. doi: 10.1038/s41598-021-03891-8. PMID: 34996976; PMCID: PMC8742055.
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