Modeling Late-Onset Sporadic Alzheimer’s Disease through BMI1 Deficiency

Flamier, Anthony; Hajjar, Jida El; Adjaye, James; Fernandes, Karl J.L.; Abdouh, Mohamed; Bernier, Gilbert

doi:10.1016/j.celrep.2018.04.097

Cited by 52 publications

(66 citation statements)

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“…BMI1 is highly expressed in mature human and mouse cortical neurons and its expression is reduced in neurons from Alzheimer's disease patients. 47,48 Furthermore, acute BMI1 knockdown in cultured human cortical neurons leads to severe neurodegeneration, 48 thus raising substantial concerns about possible side effects of BMI1 inhibitors on normal brain function. To investigate this, we generated day in vitro 35 post-mitotic cortical neurons through directed differentiation of human embryonic stem cells or induced pluripotent stem cells.…”

Section: Resultsmentioning

confidence: 99%

“…To investigate this, we generated day in vitro 35 post-mitotic cortical neurons through directed differentiation of human embryonic stem cells or induced pluripotent stem cells. 48 Cultured neurons were treated with 100 nM of PTC596 or A1016 for 24 h and analyzed by immunoblot. Notably, drug-treated neurons were apparently healthy and presented elevated levels of BMI1 and H2A ub , suggesting a concomitant increase in the biochemical activity of the PRC1 (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…To dissect the pioneer molecular changes resulting from BMI1 inactivation, we targeted BMI1 exon 1 using CRISPR/Cas9 technology to generate BMI1 knockout (BMI1 KO ) GBM cells. 48 A non-targeting template guide RNA was used as a negative control. Control (BMI1 +/+ ) and BMI1 KO cells were collected 24 h post-transfection for western blot and RNAseq analyses.…”

Section: Resultsmentioning

confidence: 99%

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Off-target effect of the BMI1 inhibitor PTC596 drives epithelial-mesenchymal transition in glioblastoma multiforme

et al. 2020

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Glioblastoma multiforme (GBM) is an incurable primary brain tumor containing a sub-population of cancer stem cells (CSCs). Polycomb Repressive Complex (PRC) proteins BMI1 and EZH2 are enriched in CSCs, promoting clonogenic growth and resistance to genotoxic therapies. We report here that when used at appropriate concentrations, pharmaceutical inhibitors of BMI1 could efficiently prevent GBM colony growth and CSC self-renewal in vitro and significantly extend lifespan in terminally ill tumor-bearing mice. Notably, molecular analyses revealed that the commonly used PTC596 molecule targeted both BMI1 and EZH2, possibly providing beneficial therapeutic effects in some contexts. On the other hand, treatment with PTC596 resulted in instant reactivation of EZH2 target genes and induction of a molecular program of epithelial-mesenchymal transition (EMT), possibly explaining the modified phenotype of some PTC596-treated tumors. Treatment with a related but more specific BMI1 inhibitor resulted in tumor regression and maintenance of cell identity. We conclude that inhibition of BMI1 alone is efficient at inducing GBM regression, and that dual inhibition of BMI1 and EZH2 using PTC596 may be also beneficial but only in specific contexts.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Off-target effect of the BMI1 inhibitor PTC596 drives epithelial-mesenchymal transition in glioblastoma multiforme

et al. 2020

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“…BMI1 heterozygous mice develop cognitive deficiency with accumulation of tau phosphorylation, Aβ plaques, and neuron loss [198]; the animals also display reductions in DDR [198]. Additionally, knockout of BMI1 in post-mitotic neurons induces Aβ deposition and tau hyperphosphorylation [199]. Collectively, evidence suggests a role of BMI1 in reducing AD via facilitating neurogenesis partially through DNA repair.…”

Section: A Role Of Dna Damage In Ad Via Affecting Neurogenesismentioning

confidence: 98%

“…BMI1 is emerging to facilitate DSB repair through both the HR and NHEJ pathways [194][195][196][197]. BMI1 protein expression is reduced in post-mortem AD brains (n = 2) in comparison to age-matched controls (n = 2) [198]; the downregulation is detected in LOAD brain but not in early-onset familial AD (FAD) [199]. BMI1 heterozygous mice develop cognitive deficiency with accumulation of tau phosphorylation, Aβ plaques, and neuron loss [198]; the animals also display reductions in DDR [198].…”

Section: A Role Of Dna Damage In Ad Via Affecting Neurogenesismentioning

confidence: 99%

Contributions of DNA Damage to Alzheimer’s Disease

Lin

Kapoor

et al. 2020

IJMS

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Alzheimer's disease (AD) is the most common type of neurodegenerative disease. Its typical pathology consists of extracellular amyloid-β (Aβ) plaques and intracellular tau neurofibrillary tangles. Mutations in the APP, PSEN1, and PSEN2 genes increase Aβ production and aggregation, and thus cause early onset or familial AD. Even with this strong genetic evidence, recent studies support AD to result from complex etiological alterations. Among them, aging is the strongest risk factor for the vast majority of AD cases: Sporadic late onset AD (LOAD). Accumulation of DNA damage is a well-established aging factor. In this regard, a large amount of evidence reveals DNA damage as a critical pathological cause of AD. Clinically, DNA damage is accumulated in brains of AD patients. Genetically, defects in DNA damage repair resulted from mutations in the BRAC1 and other DNA damage repair genes occur in AD brain and facilitate the pathogenesis. Abnormalities in DNA damage repair can be used as diagnostic biomarkers for AD. In this review, we discuss the association, the causative potential, and the biomarker values of DNA damage in AD pathogenesis.Int. J. Mol. Sci. 2020, 21, 1666 2 of 26 amyloid (senile) plaques in AD brain [9][10][11]. Furthermore, CDK5 activities affect DNA damage response [12], supporting a linkage of DNA damage with AD [13,14].Aβ peptides are directly produced by sequential cleavages of APP by βand γ-secretase; the proteolytic c-terminal fragment of APP (CTFβ) of β-secretase is cleaved within the cell membrane by γ-secretase to generate neurotoxic Aβ peptides with length ranging from 38-43 residues [15][16][17][18][19]. The 40 residue Aβ peptide (Aβ 1-40 ) is the major product, accounting for more than 50% of Aβ peptides [9,17]. Although the Aβ 1-42 peptide consists of less than 10% of Aβ peptides [16,17], it is more neurotoxic and associates with a higher risk of AD because of its propensity of aggregation [9]. The importance of Aβ in AD pathogenesis is illustrated by mutations of APP, PSEN1, and PREN2 genes in familial AD with the latter two encoding the presenilin 1 and presenilin 2 subunit of γ-secretase. Individuals with these mutations develop early onset dementia in an autosomal-dominant manner [20]; the typical onset starts between 30 and 50 years of age in PSEN1 mutant carriers with some being affected at in their 20s [20,21]. γ-secretase with mutant presenilin 1 or presenilin 2 subunit favors Aβ 1-42 production [16,17]. These genetic observations led to formation of the amyloid cascade hypothesis, in which abnormal Aβ drives AD pathogenesis via regulating other pathological events including tau pathology [22][23][24][25][26][27]. This hypothesis is supported by the similar pathological features between familial AD and sporadic late onset AD (LOAD) [20]. Although familial AD constitutes less than 1% of AD cases [28,29], the hypothesis has been widely accepted to guide research in advancing the understanding of both familial AD and LOAD in the past two decades [30,31].Nonetheless, it is becoming in...

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Transposable elements as new players in neurodegenerative diseases

et al. 2021

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Neurodegenerative diseases (NDs), including the most prevalent Alzheimer’s disease and Parkinson disease, share common pathological features. Despite decades of gene‐centric approaches, the molecular mechanisms underlying these diseases remain widely elusive. In recent years, transposable elements (TEs), long considered ‘junk’ DNA, have gained growing interest as pathogenic players in NDs. Age is the major risk factor for most NDs, and several repressive mechanisms of TEs, such as heterochromatinization, fail with age. Indeed, heterochromatin relaxation leading to TE derepression has been reported in various models of neurodegeneration and NDs. There is also evidence that certain pathogenic proteins involved in NDs (e.g., tau, TDP‐43) may control the expression of TEs. The deleterious consequences of TE activation are not well known but they could include DNA damage and genomic instability, altered host gene expression, and/or neuroinflammation, which are common hallmarks of neurodegeneration and aging. TEs might thus represent an overlooked pathogenic culprit for both brain aging and neurodegeneration. Certain pathological effects of TEs might be prevented by inhibiting their activity, pointing to TEs as novel targets for neuroprotection.

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Modeling Late-Onset Sporadic Alzheimer’s Disease through BMI1 Deficiency

Cited by 52 publications

References 52 publications

Off-target effect of the BMI1 inhibitor PTC596 drives epithelial-mesenchymal transition in glioblastoma multiforme

Off-target effect of the BMI1 inhibitor PTC596 drives epithelial-mesenchymal transition in glioblastoma multiforme

Contributions of DNA Damage to Alzheimer’s Disease

Transposable elements as new players in neurodegenerative diseases

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