Telomerase Activity is Downregulated Early During Human Brain Development

Abstract

Changes in hTERT splice variant expression have been proposed to facilitate the decrease of telomerase activity during fetal development in various human tissues. Here, we analyzed the expression of telomerase RNA (hTR), wild type and α-spliced hTERT in developing human fetal brain (post conception weeks, pcw, 6–19) and in young and old cortices using qPCR and correlated it to telomerase activity measured by TRAP assay. Decrease of telomerase activity occurred early during brain development and correlated strongest to decreased hTR expression. The expression of α-spliced hTERT increased between pcw 10 and 19, while that of wild type hTERT remained unchanged. Lack of expression differences between young and old cortices suggests that most changes seem to occur early during human brain development. Using in vitro differentiation of neural precursor stem cells (NPSCs) derived at pcw 6 we found a decrease in telomerase activity but no major expression changes in telomerase associated genes. Thus, they do not seem to model the mechanisms for the decrease in telomerase activity in fetal brains. Our results suggest that decreased hTR levels, as well as transient increase in α-spliced hTERT, might both contribute to downregulation of telomerase activity during early human brain development between 6 and 17 pcw.

Decreased mTOR signalling reduces mitochondrial ROS in brain via accumulation of the telomerase protein TERT within mitochondria

“…We and others had previously shown that the telomerase protein TERT is able to improve mitochondrial function and to decrease oxidative stress [1–3]. In addition, it was demonstrated that although telomerase activity is downregulated early during human brain development [5, 7] and soon after postnatal development in mouse brains [6], TERT protein persists in adult mammalian brain and can enter neuronal mitochondria in vivo [10]. So far, oxidative stress, radiation or treatment with chemotherapeutic drugs such as etoposide have been shown to function as triggers for mitochondrial localisation of TERT in cellular models [1–3].…”

“…One of them is the shuttling of the protein part TERT to mitochondria where it has been shown to protect cells from oxidative stress, and reduce mito-chondrial DNA damage and apoptosis [1–3]. Telomerase activity is high in the embryonic brain but downregulated early during human brain development and postnatally in mice [4–7]. However, the telomerase protein TERT has been shown to persist in adult mammalian brains [6, 7–11].…”

“…Telomerase activity is high in the embryonic brain but downregulated early during human brain development and postnatally in mice [4–7]. However, the telomerase protein TERT has been shown to persist in adult mammalian brains [6, 7–11]. We recently demonstrated that in human hippocampal neurons from late stage Alzheimer's disease (Braak stage 6) a higher amount of TERT protein accumulates within mitochondria compared to those from age-matched healthy brains (Braak stage 0) [10].…”

Non-canonical Roles of Telomerase: Unraveling the Imbroglio

“…The question remains about the relevance of the antioxidative function of hTERT during development or in response to stresses in adult in specific tissues or in cancer cells. Recent results indicate that the protein TERT persists in the adult brain while telomerase activity was shut-down before birth (Ulaner et al, 1998;Iannilli et al, 2013;Ishaq et al, 2016;Miwa et al, 2016;Miwa and Saretzki, 2017). In mouse, TERT is expressed in several regions of the adult brain such as the olfactory bulb, hippocampus, cortex, and cerebellum (Caporaso et al, 2003;Flanary and Streit, 2003;Eitan et al, 2012).…”

Leukocyte telomere shortening in Huntington's disease

“…A cellular multi-protein complex, called telomerase, counteracts telomere shortening [4,5]. Usually present in the early stages of embryonic development, its activity is silenced in several human somatic tissues immediately after birth [6]. As a consequence, in the telomeres shorten progressively in the replicating cells of adult tissues (including skin, kidney, liver, blood vessels, and peripheral leukocytes); this phenomenon is thought to indicate cellular age and reflect an organism's biological age [7][8][9].…”