The wonderful new world of telomerase in the brain and its possible implications for neurodegenerative diseases
Main Article Content
Abstract
While telomerase is best known as the enzyme that maintains telomeres in dividing cells a number of TERT (Telomerase Reverse Transcriptase)-related non-canonical functions have been described. These functions are implicated in tumour development and stress response and recently have also been demonstrated in the brain. In contrast to other cells and tissues, in the brain the telomerase RNA component TERC is downregulated early during development resulting in the loss of telomerase activity in most cells except for neural stem cells. In contrast, the presence of the telomerase protein TERT persists during lifetime in neurons of the human brain. Although we are far from understanding the role of telomerase in the brain, the review aims to summarise our current knowledge. In addition to physiological functions in healthy neurons, there might be implications for neurodegenerative diseases.
Article Details
How to Cite
SARETZKI, Gabriele.
The wonderful new world of telomerase in the brain and its possible implications for neurodegenerative diseases.
Medical Research Archives, [S.l.], v. 8, n. 7, july 2020.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/2187>. Date accessed: 31 dec. 2024.
doi: https://doi.org/10.18103/mra.v8i7.2187.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. Casacuberta E. Drosophila: Retrotransposons Making up Telomeres. Viruses. 2017 Jul; 9(7): 192. doi: 10.3390/v9070192
2. Ulaner GA, Hu JF, Vu TH, Giudice LC, Hoffman AR, Telomerase activity in human development is regulated by human telomerase reverse transcriptase (hTERT) transcription and by alternate splicing of hTERT transcripts. Cancer Res. 1998, 58, 4168–4172.
3. Collins K. Physiological Assembly and Activity of Human Telomerase Complexes. Mech Ageing Dev. 2008;129(1-2):91-98.
4. Daniel M, Peek GW, Tollefsbol TO, Regulation of the human catalytic subunit of telomerase (hTERT) Gene. 2012;498(2): 135–146.
5. Ahmed S, Passos JF, Birket MJ, et al. Telomerase does not counteract telomere shortening but protects mitochondrial function under oxidative stress. J Cell Sci. 2008; 121:1046-1053
6. Chiang YJ, Hemann MT, Hathcock KS, et al. Expression of Telomerase RNA Template, but Not Telomerase Reverse Transcriptase, Is Limiting for Telomere Length Maintenance In Vivo. Mol Cell Biol. 2004;24(16): 7024–7031.
7. Wong JM, Collins K Telomerase RNA level limits telomere maintenance in X-linked dyskeratosis congenita. Genes Dev. 2006 20(20): 2848–2858
8. Saretzki G. Extra-telomeric Functions of Human Telomerase: Cancer, Mitochondria and Oxidative Stress. Curr Pharm Des. 2014; 20:6386-6403.
9. Ségal-Bendirdjian E, Vincent Geli V Non-canonical Roles of Telomerase: Unraveling the Imbroglio. Front Cell Dev Biol. 2019;7:332.
10. Jaiswal RK, Pramod K, Pramod KY Telomerase and its extracurricular activities. Cell Mol Biol Lett. 2013;18(4):538–554.
11. Santos JH, Meyer JN, Skorvaga M, Annab LA, Van Houten B. Mitochondrial hTERT exacerbates free-radical-mediated mtDNA damage. Aging Cell. 2004; 3:399–411.
12. Haendeler J, Dröse S, Büchner N, et al. Mitochondrial telomerase reverse transcriptase binds to and protects mitochondrial DNA and function from damage. Arterioscler Thromb Vasc Biol. 2009;29:929-935.
13. Singhapol C, Pal D, Czapiewski R, et al. Mitochondrial telomerase protects cancer cells from nuclear DNA damage and apoptosis. PloS One. 2013;8(1):e52989.
14. Schmidt JC, Cech, TR. Human telomerase: biogenesis, trafficking, recruitment, and activation. Genes Dev. 2015;29(11):1095–1105.
15. Sharma NK, Reyes A, Green P, et al. Human telomerase acts as a hTR-inde-pendent reverse transcriptase in mitochondria. Nucleic Acids Res. 2012;40:712-725.
16. Spilsbury A, Miwa, S, Attems, J, Saretzki G. The role of telomerase protein TERT in Alzheimer’s disease and in tau-related pathology in vitro. J of Neuroscience. 2015;35(4):1659-74
17. Ishaq A, Hanson PS, Morris CM, Saretzki G. Telomerase Activity is Downregulated Early During Human Brain Development. Genes (Basel). 2016;7(6)pii: E27.
18. Eitan E, Tamar A, Yossi G, Peleg R, Braiman A, Priel E. Expression of functional alternative telomerase RNA component gene in mouse brain and in motor neurons cells protects from oxidative stress. Oncotarget. 2016;7(48):78297-78309.
19. Miwa S, Czapiewski R, Wan T et al. Decreased mTOR signalling reduces mitochondrial ROS in brain via accumulation of the telomerase protein TERT within mito¬chondria. Aging. 2016;8:2551-2567.
20. Eitan E, Braverman C, Tichon A, et al. Excitotoxic and Radiation Stress Increase TERT Levels in the Mitochondria and Cytosol of Cerebellar Purkinje Neurons. Cerebellum. 2016;15(4): 509–517.
21. Klapper W, Shin T, Mattson MP. Differential regulation of telo¬merase activity and TERT expression during brain development in mice. J Neurosci Res. 2001;64:252-260.
22. Lopes da Fonseca T, Villar-Piqué A, Outeiro TF. The Interplay between Alpha-Synuclein Clearance and Spreading. Biomolecules. 2015;5(2):435-71
23. Im E Yoon JB, Lee HW, Chung KC. Human Telomerase Reverse Transcriptase (hTERT) Positively Regulates 26S Proteasome Activity. J Cell Physiol. 2017;232(8):2083-2093.
24. Ali M, Devkota S, Roh JI, Lee J, Lee HW Telomerase reverse transcriptase induces basal and amino acid starvation-induced autophagy through mTORC1.Biochem Biophys Res Commun. 2016;478(3):1198-2004.
25. Kawauchi K, Ihjima K, Yamada O. IL-2 increases human telo¬merase reverse transcriptase activity transcriptionally and posttrans¬lationally through phosphatidylinositol 3’-kinase/Akt, heat shock protein 90, and mammalian target of rapamycin in transformed NK cells. J Immunol. 2005;174:5261-5269.
26. Sundin T, Peffley DM, Hentosh P. Disruption of an hTERT-mTOR-RAPTOR protein complex by a phytochemical perillyl alcohol and rapamycin. Mol Cell Biochem. 2013;375(1-2): 97-104.
27. 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;4, 313–329.
28. 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;9(1):18118.
29. Whittemore K, Derevyanko A, Martinez P, Serrano R, Pumarola M, Bosch F, Blasco MA. Telomerase gene therapy ameliorates the effects of neurodegeneration associated to short telomeres in mice. Aging (Albany NY) 2019;11(10):2916–2948.
2. Ulaner GA, Hu JF, Vu TH, Giudice LC, Hoffman AR, Telomerase activity in human development is regulated by human telomerase reverse transcriptase (hTERT) transcription and by alternate splicing of hTERT transcripts. Cancer Res. 1998, 58, 4168–4172.
3. Collins K. Physiological Assembly and Activity of Human Telomerase Complexes. Mech Ageing Dev. 2008;129(1-2):91-98.
4. Daniel M, Peek GW, Tollefsbol TO, Regulation of the human catalytic subunit of telomerase (hTERT) Gene. 2012;498(2): 135–146.
5. Ahmed S, Passos JF, Birket MJ, et al. Telomerase does not counteract telomere shortening but protects mitochondrial function under oxidative stress. J Cell Sci. 2008; 121:1046-1053
6. Chiang YJ, Hemann MT, Hathcock KS, et al. Expression of Telomerase RNA Template, but Not Telomerase Reverse Transcriptase, Is Limiting for Telomere Length Maintenance In Vivo. Mol Cell Biol. 2004;24(16): 7024–7031.
7. Wong JM, Collins K Telomerase RNA level limits telomere maintenance in X-linked dyskeratosis congenita. Genes Dev. 2006 20(20): 2848–2858
8. Saretzki G. Extra-telomeric Functions of Human Telomerase: Cancer, Mitochondria and Oxidative Stress. Curr Pharm Des. 2014; 20:6386-6403.
9. Ségal-Bendirdjian E, Vincent Geli V Non-canonical Roles of Telomerase: Unraveling the Imbroglio. Front Cell Dev Biol. 2019;7:332.
10. Jaiswal RK, Pramod K, Pramod KY Telomerase and its extracurricular activities. Cell Mol Biol Lett. 2013;18(4):538–554.
11. Santos JH, Meyer JN, Skorvaga M, Annab LA, Van Houten B. Mitochondrial hTERT exacerbates free-radical-mediated mtDNA damage. Aging Cell. 2004; 3:399–411.
12. Haendeler J, Dröse S, Büchner N, et al. Mitochondrial telomerase reverse transcriptase binds to and protects mitochondrial DNA and function from damage. Arterioscler Thromb Vasc Biol. 2009;29:929-935.
13. Singhapol C, Pal D, Czapiewski R, et al. Mitochondrial telomerase protects cancer cells from nuclear DNA damage and apoptosis. PloS One. 2013;8(1):e52989.
14. Schmidt JC, Cech, TR. Human telomerase: biogenesis, trafficking, recruitment, and activation. Genes Dev. 2015;29(11):1095–1105.
15. Sharma NK, Reyes A, Green P, et al. Human telomerase acts as a hTR-inde-pendent reverse transcriptase in mitochondria. Nucleic Acids Res. 2012;40:712-725.
16. Spilsbury A, Miwa, S, Attems, J, Saretzki G. The role of telomerase protein TERT in Alzheimer’s disease and in tau-related pathology in vitro. J of Neuroscience. 2015;35(4):1659-74
17. Ishaq A, Hanson PS, Morris CM, Saretzki G. Telomerase Activity is Downregulated Early During Human Brain Development. Genes (Basel). 2016;7(6)pii: E27.
18. Eitan E, Tamar A, Yossi G, Peleg R, Braiman A, Priel E. Expression of functional alternative telomerase RNA component gene in mouse brain and in motor neurons cells protects from oxidative stress. Oncotarget. 2016;7(48):78297-78309.
19. Miwa S, Czapiewski R, Wan T et al. Decreased mTOR signalling reduces mitochondrial ROS in brain via accumulation of the telomerase protein TERT within mito¬chondria. Aging. 2016;8:2551-2567.
20. Eitan E, Braverman C, Tichon A, et al. Excitotoxic and Radiation Stress Increase TERT Levels in the Mitochondria and Cytosol of Cerebellar Purkinje Neurons. Cerebellum. 2016;15(4): 509–517.
21. Klapper W, Shin T, Mattson MP. Differential regulation of telo¬merase activity and TERT expression during brain development in mice. J Neurosci Res. 2001;64:252-260.
22. Lopes da Fonseca T, Villar-Piqué A, Outeiro TF. The Interplay between Alpha-Synuclein Clearance and Spreading. Biomolecules. 2015;5(2):435-71
23. Im E Yoon JB, Lee HW, Chung KC. Human Telomerase Reverse Transcriptase (hTERT) Positively Regulates 26S Proteasome Activity. J Cell Physiol. 2017;232(8):2083-2093.
24. Ali M, Devkota S, Roh JI, Lee J, Lee HW Telomerase reverse transcriptase induces basal and amino acid starvation-induced autophagy through mTORC1.Biochem Biophys Res Commun. 2016;478(3):1198-2004.
25. Kawauchi K, Ihjima K, Yamada O. IL-2 increases human telo¬merase reverse transcriptase activity transcriptionally and posttrans¬lationally through phosphatidylinositol 3’-kinase/Akt, heat shock protein 90, and mammalian target of rapamycin in transformed NK cells. J Immunol. 2005;174:5261-5269.
26. Sundin T, Peffley DM, Hentosh P. Disruption of an hTERT-mTOR-RAPTOR protein complex by a phytochemical perillyl alcohol and rapamycin. Mol Cell Biochem. 2013;375(1-2): 97-104.
27. 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;4, 313–329.
28. 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;9(1):18118.
29. Whittemore K, Derevyanko A, Martinez P, Serrano R, Pumarola M, Bosch F, Blasco MA. Telomerase gene therapy ameliorates the effects of neurodegeneration associated to short telomeres in mice. Aging (Albany NY) 2019;11(10):2916–2948.