Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
The Cerebellum
Published in: The Cerebellum 4/2016

01-08-2016 | Original Paper

Excitotoxic and Radiation Stress Increase TERT Levels in the Mitochondria and Cytosol of Cerebellar Purkinje Neurons

Authors: Erez Eitan, Carmel Braverman, Ailone Tichon, Daniel Gitler, Emmette R. Hutchison, Mark P. Mattson, Esther Priel

Published in: The Cerebellum | Issue 4/2016

Login to get access

Abstract

Telomerase reverse transcriptase (TERT) is the catalytic subunit of telomerase, an enzyme that elongates telomeres at the ends of chromosomes during DNA replication. Recently, it was shown that TERT has additional roles in cell survival, mitochondrial function, DNA repair, and Wnt signaling, all of which are unrelated to telomeres. Here, we demonstrate that TERT is enriched in Purkinje neurons, but not in the granule cells of the adult mouse cerebellum. TERT immunoreactivity in Purkinje neurons is present in the nucleus, mitochondria, and cytoplasm. Furthermore, TERT co-localizes with mitochondrial markers, and immunoblot analysis of protein extracts from isolated mitochondria and synaptosomes confirmed TERT localization in mitochondria. TERT expression in Purkinje neurons increased significantly in response to two stressors: a sub-lethal dose of X-ray radiation and exposure to a high glutamate concentration. While X-ray radiation increased TERT levels in the nucleus, glutamate exposure elevated TERT levels in mitochondria. Our findings suggest that in mature Purkinje neurons, TERT is present both in the nucleus and in mitochondria, where it may participate in adaptive responses of the neurons to excitotoxic and radiation stress.
Appendix
Available only for authorised users
Literature
1.
Cohen SB et al. Protein composition of catalytically active human telomerase from immortal cells. Science. 2007;315(5820):1850–3.CrossRefPubMed
2.
Klapper W, Shin T, Mattson MP. Differential regulation of telomerase activity and TERT expression during brain development in mice. J Neurosci Res. 2001;64(3):252–60.CrossRefPubMed
3.
Caporaso GL et al. Telomerase activity in the subventricular zone of adult mice. Mol Cell Neurosci. 2003;23(4):693–702.CrossRefPubMed
4.
Flanary BE, Streit WJ. Telomeres shorten with age in rat cerebellum and cortex in vivo. J Anti Aging Med. 2003;6(4):299–308.CrossRefPubMed
5.
Eitan E et al. Telomerase expression in adult and old mouse Purkinje neurons. Rejuvenation Res. 2012;15(2):206–9.CrossRefPubMed
6.
Spilsbury A et al. The role of telomerase protein TERT in Alzheimer’s disease and in Tau-related pathology in vitro. J Neurosci. 2015;35(4):1659–74.CrossRefPubMedPubMedCentral
7.
Santos JH, Meyer JN, Van Houten B. Mitochondrial localization of telomerase as a determinant for hydrogen peroxide-induced mitochondrial DNA damage and apoptosis. Hum Mol Genet. 2006;15(11):1757–68.CrossRefPubMed
8.
Iannilli F et al. Cytoplasmic TERT associates to RNA granules in fully mature neurons: role in the translational control of the cell cycle inhibitor p15INK4B. PLoS One. 2013;8(6):e66602.CrossRefPubMedPubMedCentral
9.
10.
Strong MA et al. Phenotypes in mTERT/ and mTERT/ mice are due to short telomeres, not telomere-independent functions of telomerase reverse transcriptase. Mol Cell Biol. 2011;31(12):2369–79.CrossRefPubMedPubMedCentral
11.
Majerska J, Sykorova E, Fajkus J. Non-telomeric activities of telomerase. Mol Biosyst. 2011;7(4):1013–23.CrossRefPubMed
12.
Kovalenko, O.A., et al., A mutant telomerase defective in nuclear-cytoplasmic shuttling fails to immortalize cells and is associated with mitochondrial dysfunction. Aging Cell, 2010.
13.
Fu W et al. The catalytic subunit of telomerase is expressed in developing brain neurons and serves a cell survival-promoting function. J Mol Neurosci. 2000;14(1–2):3–15.CrossRefPubMed
14.
Mattson MP, Klapper W. Emerging roles for telomerase in neuronal development and apoptosis. J Neurosci Res. 2001;63(1):1–9.CrossRefPubMed
15.
Lee J et al. TERT promotes cellular and organismal survival independently of telomerase activity. Oncogene. 2008;27(26):3754–60.CrossRefPubMed
16.
Kang HJ et al. Ectopic expression of the catalytic subunit of telomerase protects against brain injury resulting from ischemia and NMDA-induced neurotoxicity. J Neurosci. 2004;24(6):1280–7.CrossRefPubMed
17.
Qu Y et al. Telomerase reverse transcriptase upregulation attenuates astrocyte proliferation and promotes neuronal survival in the hypoxic-ischemic rat brain. Stroke. 2011;42(12):3542–50.CrossRefPubMed
18.
Zhao F et al. The neuroprotective role of TERT via an antiapoptotic mechanism in neonatal rats after hypoxia-ischemia brain injury. Neurosci Lett. 2012;515(1):39–43.CrossRefPubMed
19.
Eitan E et al. Novel telomerase-increasing compound in mouse brain delays the onset of amyotrophic lateral sclerosis. EMBO Mol Med. 2012;4(4):313–29.CrossRefPubMedPubMedCentral
20.
Lein ES et al. Genome-wide atlas of gene expression in the adult mouse brain. Nature. 2007;445(7124):168–76.CrossRefPubMed
21.
Li P et al. Mitochondrial translocation of human telomerase reverse transcriptase in cord blood mononuclear cells of newborns with gestational diabetes mellitus mothers. Diabetes Res Clin Pract. 2014;103(2):310–8.CrossRefPubMed
22.
Haendeler J et al. Mitochondrial telomerase reverse transcriptase binds to and protects mitochondrial DNA and function from damage. Arterioscler Thromb Vasc Biol. 2009;29(6):929–35.CrossRefPubMed
23.
Mitchell M et al. Structural basis for telomerase catalytic subunit TERT binding to RNA template and telomeric DNA. Nat Struct Mol Biol. 2010;17(4):513–8.CrossRefPubMed
24.
25.
Rube CE et al. DNA double-strand break repair of blood lymphocytes and normal tissues analysed in a preclinical mouse model: implications for radiosensitivity testing. Clin Cancer Res. 2008;14(20):6546–55.CrossRefPubMed
26.
Ward MW et al. Mitochondrial membrane potential and glutamate excitotoxicity in cultured cerebellar granule cells. J Neurosci. 2000;20(19):7208–19.PubMed
27.
Platt SR. The role of glutamate in central nervous system health and disease—a review. Vet J. 2007;173(2):278–86.CrossRefPubMed
28.
Parkinson EK, Fitchett C, Cereser B. Dissecting the non-canonical functions of telomerase. Cytogenet Genome Res. 2008;122(3–4):273–80.PubMed
29.
Sharma GG et al. hTERT associates with human telomeres and enhances genomic stability and DNA repair. Oncogene. 2003;22(1):131–46.CrossRefPubMed
30.
Wadiche JI, Jahr CE. Multivesicular release at climbing fiber-Purkinje cell synapses. Neuron. 2001;32(2):301–13.CrossRefPubMed
31.
Zhang, B., et al., Deficiency of telomerase activity aggravates the blood–brain barrier disruption and neuroinflammatory responses in a model of experimental stroke. J Neurosci Res, 2010
32.
Masutomi K et al. The telomerase reverse transcriptase regulates chromatin state and DNA damage responses. Proc Natl Acad Sci U S A. 2005;102(23):8222–7.CrossRefPubMedPubMedCentral
33.
34.
35.
36.
Aalfs CM et al. The Hoyeraal-Hreidarsson syndrome: the fourth case of a separate entity with prenatal growth retardation, progressive pancytopenia and cerebellar hypoplasia. Eur J Pediatr. 1995;154(4):304–8.CrossRefPubMed
37.
Metcalfe JA et al. Accelerated telomere shortening in ataxia telangiectasia. Nat Genet. 1996;13(3):350–3.CrossRefPubMed
38.
Eitan E, Hutchison ER, Mattson MP. Telomere shortening in neurological disorders: an abundance of unanswered questions. Trends Neurosci. 2014;37(5):256–63.CrossRefPubMedPubMedCentral
39.
Liu Y et al. The telomerase reverse transcriptase is limiting and necessary for telomerase function in vivo. Curr Biol. 2000;10(22):1459–62.CrossRefPubMed
40.
Zehorai E et al. Glutamate regulates the activity of topoisomerase I in mouse cerebellum. Mol Neurobiol. 2008;38(3):242–52.CrossRefPubMed
41.
Auer B et al. Intracellular distribution of DNA topoisomerase I in fibroblasts from patients with Fanconi’s anaemia. Hum Genet. 1982;61(4):369–71.CrossRefPubMed
42.
Bendetz-Nezer S, Gazit A, Priel E. DNA topoisomerase I as one of the cellular targets of certain tyrphostin derivatives. Mol Pharmacol. 2004;66(3):627–34.PubMed
43.
44.
Kaufmann SH, Svingen PA. Immunoblot analysis and band depletion assays. Methods Mol Biol. 1999;94:253–68.PubMed
Metadata
Title
Excitotoxic and Radiation Stress Increase TERT Levels in the Mitochondria and Cytosol of Cerebellar Purkinje Neurons
Authors
Erez Eitan
Carmel Braverman
Ailone Tichon
Daniel Gitler
Emmette R. Hutchison
Mark P. Mattson
Esther Priel
Publication date
01-08-2016
Publisher
Springer US
Published in
The Cerebellum / Issue 4/2016
Print ISSN: 1473-4222
Electronic ISSN: 1473-4230
DOI
https://doi.org/10.1007/s12311-015-0720-6

Other articles of this Issue 4/2016

The Cerebellum 4/2016 Go to the issue

Cerebellar Classics XII

The Cerebellar System and What it Signifies from a Biological Perspective, by Professor Christofredo Jakob (English Translation)

Original Paper

Psychosis in Machado–Joseph Disease: Clinical Correlates, Pathophysiological Discussion, and Functional Brain Imaging. Expanding the Cerebellar Cognitive Affective Syndrome

Original Paper

Contribution of the Cerebellum in Cue-Dependent Force Changes During an Isometric Precision Grip Task

Original Paper

Strabismus and Micro-Opsoclonus in Machado-Joseph Disease

Original Paper

Cytokines in Machado Joseph Disease/Spinocerebellar Ataxia 3

Review

Dysplastic Cerebellar Epilepsy: Complete Seizure Control Following Resection of a Ganglioglioma