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Telomere shortening leads to earlier age of onset in ALS mice.

ABSTRACT: Telomere shortening has been linked to a variety of neurodegenerative diseases. Recent evidence suggests that reduced telomerase expression results in shorter telomeres in leukocytes from sporadic patients with amyotrophic lateral sclerosis (ALS) compared with healthy controls. Here, we have characterized telomere length in microglia, astroglia and neurons in human post mortem brain tissue from ALS patients and healthy controls. Moreover, we studied the consequences of telomerase deletion in a genetic mouse model for ALS. We found a trend towards longer telomeres in microglia in the brains of ALS patients compared to non-neurologic controls. Knockout of telomerase leading to telomere shortening accelerated the ALS phenotype inSOD1G93A-transgenic mice. Our results suggest that telomerase dysfunction might contribute to the age-related risk for ALS.

SUBMITTER: Linkus B

PROVIDER: S-EPMC4789589 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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Telomere shortening leads to earlier age of onset in ALS mice.

Linkus Birgit B Wiesner Diana D Meßner Martina M Karabatsiakis Alexander A Scheffold Annika A Rudolph K Lenhard KL Thal Dietmar R DR Weishaupt Jochen H JH Ludolph Albert C AC Danzer Karin M KM

Aging 20160201 2

Telomere shortening has been linked to a variety of neurodegenerative diseases. Recent evidence suggests that reduced telomerase expression results in shorter telomeres in leukocytes from sporadic patients with amyotrophic lateral sclerosis (ALS) compared with healthy controls. Here, we have characterized telomere length in microglia, astroglia and neurons in human post mortem brain tissue from ALS patients and healthy controls. Moreover, we studied the consequences of telomerase deletion in a g ...[more]

PMID: 26978042

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Project description:BackgroundOocytes may undergo two types of aging. The first is induced by exposure to an aged ovarian microenvironment before being ovulated, known as 'reproductive or maternal aging', and the second by either a prolonged stay in the oviduct before fertilization or in vitro aging prior to insemination, known as 'postovulatory aging'. However, the molecular mechanisms underlying these aging processes remain to be elucidated. As telomere shortening in cultured somatic cells triggers replicative senescence, telomere shortening in oocytes during reproductive and postovulatory aging may predict developmental competence. This study aimed to ascertain the mechanisms underlying altered telomere biology in mouse oocytes during reproductive and postovulatory aging.MethodsWe studied Tert expression patterns, telomerase activity, cytosolic reactive oxygen species (ROS) production, and telomere length in fresh oocytes from young versus reproductively-aged female mice retrieved from oviducts at 14 h post-human chorionic gonadotropin (hCG), in vivo or in vitro postovulatory-aged mouse oocytes at 23 h post-hCG. Oocytes were collected from super-ovulated C57BL/6 J mice of 6-8 weeks or 42-48 weeks of age. mRNA and protein expressions of the Tert gene were quantified using real-time quantitative reverse transcriptase polymerase chain reaction (Q-PCR) and immunochemistry. Telomerase activity was measured by a telomeric repeat amplification protocol assay, while telomere length was measured by Q-PCR and quantitative fluorescence in situ hybridization analyses.ResultsThe abundance of Tert expression in oocytes significantly decreased during reproductive and postovulatory aging. Immunofluorescent staining clearly demonstrated an altered pattern and intensity of TERT protein expression in oocytes during reproductive aging. Furthermore, relative telomerase activity (RTA) in oocytes from reproductively-aged females was significantly lower than that in oocytes from young females. In contrast, RTA in postovulatory-aged oocytes was similar to that in fresh oocytes. Oocytes from reproductively-aged females and postovulatory-aged oocytes showed higher ROS levels than oocytes from young females. Relative telomere length (RTL) was remarkably shorter in oocytes from reproductively-aged females compared to oocytes from young females. However, postovulatory aging had no significant effect on RTL of oocytes.ConclusionsLong-term adverse effects of low telomerase activity and increased ROS exposure are likely associated with telomere shortening in oocytes from reproductively-aged female mice.

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Telomere shortening leads to earlier age of onset in ALS mice.

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Telomere shortening leads to earlier age of onset in ALS mice.

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