Different requirements of functional telomeres in neural stem cells and terminally differentiated neurons

Lobanova, Anastasia; She, Robert; Pieraut, Simon; C, Clapp; Maximov, Anton; Denchi, Eros Lazzerini

doi:10.1101/gad.295402.116

Cited by 24 publications

(16 citation statements)

References 60 publications

(68 reference statements)

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“…These results suggest that proper telomere maintenance is essential to maintain the proliferative capacity of NPCs. In support of this notion, telomere end-protection is critical for NPC survival during brain development, as removal of either TRF2 or POT1a elicits DNA damage signaling and massive cell death in neuronal stem cells of developing murine brains [100][101][102] . Taken together, these observations suggest that proper telomere function is required for proliferation of neuronal progenitors and neurogenesis, and further support our hypothesis that telomere dysfunction may underlie neural development defects in MCPH1 patients bearing mutated MCPH1.…”

Section: Discussionmentioning

confidence: 89%

Microcephalin 1/BRIT1-TRF2 interaction promotes telomere replication and repair, linking telomere dysfunction to primary microcephaly

et al. 2020

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Telomeres protect chromosome ends from inappropriately activating the DNA damage and repair responses. Primary microcephaly is a key clinical feature of several human telomere disorder syndromes, but how microcephaly is linked to dysfunctional telomeres is not known. Here, we show that the microcephalin 1/BRCT-repeats inhibitor of hTERT (MCPH1/BRIT1) protein, mutated in primary microcephaly, specifically interacts with the TRFH domain of the telomere binding protein TRF2. The crystal structure of the MCPH1–TRF2 complex reveals that this interaction is mediated by the MCPH1 330YRLSP334 motif. TRF2-dependent recruitment of MCPH1 promotes localization of DNA damage factors and homology directed repair of dysfunctional telomeres lacking POT1-TPP1. Additionally, MCPH1 is involved in the replication stress response, promoting telomere replication fork progression and restart of stalled telomere replication forks. Our work uncovers a previously unrecognized role for MCPH1 in promoting telomere replication, providing evidence that telomere replication defects may contribute to the onset of microcephaly.

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Section: Discussionmentioning

confidence: 89%

Microcephalin 1/BRIT1-TRF2 interaction promotes telomere replication and repair, linking telomere dysfunction to primary microcephaly

et al. 2020

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“…The role of telomere biology in brain development has been evaluated in a conditional knockout of the shelterin protein TRF2 mouse model. 19 By knocking out TRF at different stages of neuronal differentiation, the authors showed that intact telomeres are essential for embryonic and adult neurogenesis. Specifically, TRF2 knockout resulted in uncapping of telomeres and a small dentate gyrus due to loss of granule cells in the hippocampus.…”

Section: Discussionmentioning

confidence: 99%

CNS manifestations in patients with telomere biology disorders

et al. 2019

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ObjectiveWe systematically evaluated CNS manifestations in patients with inherited telomere biology disorders (TBDs) to better understand the clinical and biological consequences of germline aberrations in telomere biology.MethodsForty-four participants with TBDs (31 dyskeratosis congenita, 12 Hoyeraal-Hreidarsson syndrome, and 1 Revesz syndrome) enrolled in an institutional review board–approved longitudinal cohort study underwent detailed clinical assessments, brain MRI, and genetic testing. Lymphocyte telomere length Z-scores were calculated to adjust for age.ResultsIn this cohort, 25/44 (57%) patients with a TBD had at least 1 structural brain abnormality or variant, most commonly cerebellar hypoplasia (39%). Twenty-one patients (48%) had neurodevelopmental disorder or psychomotor abnormality. Twelve had psychiatric diagnoses, including depression and/or anxiety disorders. Other findings such as hypomyelination, prominent cisterna magna, and cavum septum pellucidum were more frequent than in the general population (p < 0.001). Shorter lymphocyte telomere length was associated with an increased number of MRI findings (p = 0.02) and neurodevelopmental abnormalities (p < 0.001). Patients with autosomal recessive or X-linked TBDs had more neurologic findings than those with autosomal dominant disease.ConclusionsStructural brain abnormalities and variants are common in TBDs, as are neurologic and psychiatric symptoms. The connection between neurodevelopment and telomere biology warrants future study.

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“…Telomerase, a reverse transcriptase, is required for embryonic and adult neurogenesis (Lobanova et al, 2017 ). To investigate whether telomerase is implicated in the E2 mediated protection of NSCs in APP/PS1 mice, we analyzed the levels of TERT and telomerase activity in 10-month-old APP/PS1 mice.…”

Section: Resultsmentioning

confidence: 99%

Estradiol Replacement at the Critical Period Protects Hippocampal Neural Stem Cells to Improve Cognition in APP/PS1 Mice

Qin

et al. 2020

Front. Aging Neurosci.

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It has been suggested that there is a critical window for estrogen replacement therapy (ERT) in postmenopausal women with Alzheimer's disease (AD); however, supporting evidence is lacking. To address this issue, we investigated the effective period for estradiol (E2) treatment using a mouse model of AD. Four-monthold female APPswe/PSEN1dE9 (APP/PS1) mice were ovariectomized (OVX) and treated with E2 for 2 months starting at the age of 4 months (early period), 6 months (mid-period), or 8 months (late period). We then evaluated hippocampal neurogenesis, β-amyloid (Aβ) accumulation, telomerase activity, and hippocampaldependent behavior. Compared to age-matched wild type mice, APP/PS1 mice with intact ovaries showed increased proliferation of hippocampal neural stem cells (NSCs) at 8 months of age and decreased proliferation of NSCs at 10 months of age; meanwhile, Aβ accumulation progressively increased with age, paralleling the reduced survival of immature neurons. OVX-induced depletion of E2 in APP/PS1 mice resulted in elevated Aβ levels accompanied by elevated p75 neurotrophin receptor (p75 NTR) expression and increased NSC proliferation at 6 months of age, which subsequently declined; accelerated reduction of immature neurons starting from 6 months of age, and reduced telomerase activity and worsened memory performance at 10 months of age. Treatment with E2 in the early period post-OVX, rather than in the mid or late period, abrogated these effects, and p75 NTR inhibition reduced the overproliferation of NSCs in 6-month-old OVX-APP/PS1 mice. Thus, E2 deficiency in young APP/PS1 mice exacerbates cognitive deficits and depletes the hippocampal NSC pool in later life; this can be alleviated by E2 treatment in the early period following OVX, which prevents Aβ/p75 NTR-induced NSC overproliferation and preserves telomerase activity.

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Different requirements of functional telomeres in neural stem cells and terminally differentiated neurons

Cited by 24 publications

References 60 publications

Microcephalin 1/BRIT1-TRF2 interaction promotes telomere replication and repair, linking telomere dysfunction to primary microcephaly

Microcephalin 1/BRIT1-TRF2 interaction promotes telomere replication and repair, linking telomere dysfunction to primary microcephaly

CNS manifestations in patients with telomere biology disorders

Estradiol Replacement at the Critical Period Protects Hippocampal Neural Stem Cells to Improve Cognition in APP/PS1 Mice

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