Age-related decline in BubR1 impairs adult hippocampal neurogenesis

Yang, Zhuo; Jun, Heechul; Choi, Chan Ii; Yoo, Ki Hyun; Cho, Chang Hoon; Hussaini, S. M. Qasim; Simmons, Ambrosia J.; Kim, Seonhee; Deursen, Jan M. van; Baker, Darren J.; Jang, Mi Hyeon

doi:10.1111/acel.12594

Cited by 32 publications

(40 citation statements)

References 6 publications

(10 reference statements)

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“…Other aneuploidogenic conditions include mosaic variegated aneuploidy syndrome, which is caused by a mutation in (a) a mitotic checkpoint component BubR1/Bub1B (type 1); (b) CEP57, which encodes a centrosomal protein (type 2) (Snape et al, ); or (c) TRIP13, which is involved in mitotic checkpoint complex silencing via Mad2 liberation (Alfieri, Chang, & Barford, ; Kaisari et al, ). A reduction in BubR1 protein in mice (BubR1 H/H mice) resulted in a systemic and neuronal progeria condition (Choi et al, ) and in impairment of adult hippocampal neurogenesis (Yang et al, ). The progeric conditions were partly ameliorated by targeted elimination/reduction of p16INK4‐positive cells (Baker et al, ), by enhancing Wnt signaling via loss of Dickkopf‐1 (Seib et al, ) or via inhibition of secreted frizzled‐related protein 3 (sFRP3) (Cho et al, ), both of which are endogenous Wnt antagonists.…”

Section: The “Amyloid‐beta Accumulation Cycle”mentioning

confidence: 99%

“Amyloid‐beta accumulation cycle” as a prevention and/or therapy target for Alzheimer's disease

et al. 2020

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The cell cycle and its regulators are validated targets for cancer drugs. Reagents that target cells in a specific cell cycle phase (e.g., antimitotics or DNA synthesis inhibitors/replication stress inducers) have demonstrated success as broad‐spectrum anticancer drugs. Cyclin‐dependent kinases (CDKs) are drivers of cell cycle transitions. A CDK inhibitor, flavopiridol/alvocidib, is an FDA‐approved drug for acute myeloid leukemia. Alzheimer's disease (AD) is another serious issue in contemporary medicine. The cause of AD remains elusive, although a critical role of latent amyloid‐beta accumulation has emerged. Existing AD drug research and development targets include amyloid, amyloid metabolism/catabolism, tau, inflammation, cholesterol, the cholinergic system, and other neurotransmitters. However, none have been validated as therapeutically effective targets. Recent reports from AD‐omics and preclinical animal models provided data supporting the long‐standing notion that cell cycle progression and/or mitosis may be a valid target for AD prevention and/or therapy. This review will summarize the recent developments in AD research: (a) Mitotic re‐entry, leading to the “amyloid‐beta accumulation cycle,” may be a prerequisite for amyloid‐beta accumulation and AD pathology development; (b) AD‐associated pathogens can cause cell cycle errors; (c) thirteen among 37 human AD genetic risk genes may be functionally involved in the cell cycle and/or mitosis; and (d) preclinical AD mouse models treated with CDK inhibitor showed improvements in cognitive/behavioral symptoms. If the “amyloid‐beta accumulation cycle is an AD drug target” concept is proven, repurposing of cancer drugs may emerge as a new, fast‐track approach for AD management in the clinic setting.

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Section: The “Amyloid‐beta Accumulation Cycle”mentioning

confidence: 99%

“Amyloid‐beta accumulation cycle” as a prevention and/or therapy target for Alzheimer's disease

et al. 2020

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“…BubR1 −/+ mice showed mitotic slippage in the cells and were colon cancer‐prone (Dai et al., 2004; Rao et al., 2005), and BubR1 H/H hypomorphic mice were identified as a model for premature aging (Baker et al., 2004). Neuronal cell division and axon growth were inhibited by siRNA‐mediated BubR1 knockdown in the mouse brain (Yang et al., 2017). The above findings in BubR1 transgenic models led to a hypothesis that mitotic errors and CIN facilitate AD‐like neurodegeneration.…”

Section: Introductionmentioning

confidence: 99%

Spontaneous development of Alzheimer's disease‐associated brain pathology in a Shugoshin‐1 mouse cohesinopathy model

et al. 2018

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SummarySpontaneous late‐onset Alzheimer's disease (LOAD) accounts for more than 95% of all human AD. As mice do not normally develop AD and as understanding on molecular processes leading to spontaneous LOAD has been insufficient to successfully model LOAD in mouse, no mouse model for LOAD has been available. Existing mouse AD models are all early‐onset AD (EOAD) models that rely on forcible expression of AD‐associated protein(s), which may not recapitulate prerequisites for spontaneous LOAD. This limitation in AD modeling may contribute to the high failure rate of AD drugs in clinical trials. In this study, we hypothesized that genomic instability facilitates development of LOAD and tested two genomic instability mice models in the brain pathology at the old age. Shugoshin‐1 (Sgo1) haploinsufficient (∓) mice, a model of chromosome instability (CIN) with chromosomal and centrosomal cohesinopathy, spontaneously exhibited a major feature of AD pathology; amyloid beta accumulation that colocalized with phosphorylated Tau, beta‐secretase 1 (BACE), and mitotic marker phospho‐Histone H3 (p‐H3) in the brain. Another CIN model, spindle checkpoint‐defective BubR1−/+ haploinsufficient mice, did not exhibit the pathology at the same age, suggesting the prolonged mitosis‐origin of the AD pathology. RNA‐seq identified ten differentially expressed genes, among which seven genes have indicated association with AD pathology or neuronal functions (e.g., ARC, EBF3). Thus, the model represents a novel model that recapitulates spontaneous LOAD pathology in mouse. The Sgo1−/+ mouse may serve as a novel tool for investigating mechanisms of spontaneous progression of LOAD pathology, for early diagnosis markers, and for drug development.

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“…Mice expressing reduced levels of the spindle assembly checkpoint (SAC) component BUBR1, which is mutated in the majority of patients with Mosaic Variegated Aneuploidy (MVA) syndrome, develop progressive aneuploidy and agerelated defects including cataracts, loss of subcutaneous fat, skeletal muscle wasting, lordokyphosis, impaired wound healing [14][15][16] and cerebral degeneration, 17 with deficits in neural progenitor proliferation and maturation. 18 In oocytes, the frequency of chromosome segregation errors in meiosis I increase with maternal aging, 19 along with a decrease in BUBR1 protein. 20 The aneuploid condition may also favor neurodegeneration during aging.…”

mentioning

confidence: 99%

Aneuploidy: Cancer strength or vulnerability?

Simonetti

Bruno

Padella

et al. 2018

Intl Journal of Cancer

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Aneuploidy is a very rare and tissue-specific event in normal conditions, occurring in a low number of brain and liver cells. Its frequency increases in age-related disorders and is one of the hallmarks of cancer. Aneuploidy has been associated with defects in the spindle assembly checkpoint (SAC). However, the relationship between chromosome number alterations, SAC genes and tumor susceptibility remains unclear. Here, we provide a comprehensive review of SAC gene alterations at genomic and transcriptional level across human cancers and discuss the oncogenic and tumor suppressor functions of aneuploidy. SAC genes are rarely mutated but frequently overexpressed, with a negative prognostic impact on different tumor types. Both increased and decreased SAC gene expression show oncogenic potential in mice. SAC gene upregulation may drive aneuploidization and tumorigenesis through mitotic delay, coupled with additional oncogenic functions outside mitosis. The genomic background and environmental conditions influence the fate of aneuploid cells. Aneuploidy reduces cellular fitness. It induces growth and contact inhibition, mitotic and proteotoxic stress, cell senescence and production of reactive oxygen species. However, aneuploidy confers an evolutionary flexibility by favoring genome and chromosome instability (CIN), cellular adaptation, stem cell-like properties and immune escape. These properties represent the driving force of aneuploid cancers, especially under conditions of stress and pharmacological pressure, and are currently under investigation as potential therapeutic targets. Indeed, promising results have been obtained from synthetic lethal combinations exploiting CIN, mitotic defects, and aneuploidy-tolerating mechanisms as cancer vulnerability.

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Age-related decline in BubR1 impairs adult hippocampal neurogenesis

Cited by 32 publications

References 6 publications

“Amyloid‐beta accumulation cycle” as a prevention and/or therapy target for Alzheimer's disease

“Amyloid‐beta accumulation cycle” as a prevention and/or therapy target for Alzheimer's disease

Spontaneous development of Alzheimer's disease‐associated brain pathology in a Shugoshin‐1 mouse cohesinopathy model

Aneuploidy: Cancer strength or vulnerability?

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