Glial pathology in a novel spontaneous mutant mouse of the <i>Eif2b5</i> gene: a vanishing white matter disease model

Terumitsu-Tsujita, Mika; Kitaura, Hiroki; Miura, Ikuo; Kiyama, Yuji; Goto, Fumiko; Muraki, Yoshiko; Ominato, Shiho; Hara, Norikazu; Simankova, A N; Bizen, Norihisa; Kashiwagi, Kazuhiro; Ito, Takuhiro; Toyoshima, Yasuko; Kakita, Akiyoshi; Manabe, Toshiya; Wakana, Shigeharu; Takebayashi, Hirohide; Igarashi, Hironaka

doi:10.1111/jnc.14887

Cited by 19 publications

(14 citation statements)

References 58 publications

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“…10 eIF2α phosphorylation is reduced, probably as a consequence of an increased GADD34-mediated negative feedback loop. [10][11][12][13] This reduction may be a compensatory measure for intrinsically reduced activity of mutated eIF2B. Our findings point to a constitutively and increasingly deregulated ISR in VWM that contribute to the chronic neurological deterioration.…”

Section: Introductionmentioning

confidence: 62%

Isocaloric low protein diet in a mouse model for vanishing white matter does not impact ISR deregulation in brain, but reveals ISR deregulation in liver

Wisse

Visser

Braak

et al. 2020

Nutritional Neuroscience

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Objective: Vanishing white matter (VWM) is a genetic brain white matter disorder caused by mutations in eIF2B. eIF2B is central in the integrated stress response (ISR), during which its activity is inhibited by various cellular stresses. VWM is a chronic progressive disease with episodes of rapid neurological deterioration provoked by stresses. VWM patients and VWM mouse models show ISR deregulation in brain, correlating with chronic disease development. ISR inhibition ameliorates the chronic disease in VWM mice. The subacute deteriorations have not been modeled yet. We hypothesized that ISR activation could worsen disease progression in mice and model the episodic neurological deterioration. Method: We chose to activate the ISR by subjecting wild-type (wt) and VWM mice to an isocaloric low protein diet. This model would allow us to investigate the contribution of ISR activation in subacute decline in VWM. Results: We found that the low protein diet did not significantly affect amino acid levels nor ISR levels in wt and VWM mouse brain. Our study serendipitously led to the discovery of increased levels of glycine, asparagine and Fgf21 mRNA in VWM mouse brain irrespective of the dietary protein content. Strikingly, the ISR was not activated by the low protein diet in the liver of VWM in contrast to wt mice, due to a modest ISR deregulation in this organ. Discussion: A model for subacute neurological deterioration in VWM was not established. Possibly, ISR deregulation in VWM results in reduced ISR responsiveness.

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Section: Introductionmentioning

confidence: 62%

Isocaloric low protein diet in a mouse model for vanishing white matter does not impact ISR deregulation in brain, but reveals ISR deregulation in liver

Wisse

Visser

Braak

et al. 2020

Nutritional Neuroscience

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“…Moreover, it has been shown that in older VWMD affected patients, Bergmann glial somata are translocated to the molecular layer whereas they should be located close to Purkinje cells, this translocation representing a hallmark of VWMD for Dooves et al [13,16]. This disease marker has also been reported in a spontaneous mutant mouse in the Eif2b5 gene called the "toy mouse" [17]. In the two foetuses, virtually absent Bergmann glia somata and processes suggested a defect of Bergmann glia development and/or maintenance from early stages of gestation.…”

Section: Discussionmentioning

confidence: 90%

Foetal onset of EIF2B related disorder in two siblings: cerebellar hypoplasia with absent Bergmann glia and severe hypomyelination

Marguet

Sauvestre²,

Lasseaux³

et al. 2020

acta neuropathol commun

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Bi-allelic pathogenic variants in genes of the EIF2B family are responsible for Childhood Ataxia with Central nervous system Hypomyelination/Vanishing White Matter disease, a progressive neurodegenerative disorder of the central white matter. Only seven molecularly proven cases with antenatal onset have been reported so far. We report for the first time the neuropathological findings obtained from two foetuses harbouring deleterious variants in the EIF2B5 gene who presented in utero growth retardation and microcephaly with simplified gyral pattern that led to a medical termination of the pregnancy at 27 and 32 weeks of gestation. Neuropathological examination confirmed microcephaly with delayed gyration, periventricular pseudo-cysts and severe cerebellar hypoplasia. Histologically, the cerebellar cortex was immature, the dentate nuclei were fragmented and myelin stains revealed almost no myelination of the infratentorial structures. Bergmann glia was virtually absent associated to a drastic decreased number of mature astrocytes in the cerebellar white matter, multiple nestin-positive immature astrocytes as well as increased numbers of PDGRFα-positive oligodendrocyte precursors. Whole exome sequencing performed in the two foetuses and their parents allowed the identification of two EIF2B5 compound heterozygous variants in the two foetuses: c.468C > G p.Ile156Met and c.1165G > A p.Val389Met, the parents being heterozygous carriers. These variants are absent in the genome Aggregation Database (gnomAD r2.0.2). Contrary to the variant Ile156Met already described in a patient with CACH syndrome, the variant p.Val389Met is novel and predicted to be deleterious using several softwares. Neuropathological findings further expand the phenotypic spectrum of the disease that very likely occurs during early gestation and may manifest from the second half of pregnancy by a severe impairment of cerebral and cerebellar development.

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“…Interestingly, modulation of the brain level of this protein by chronic Li has been reported in rats 29 . Furthermore, a mutant mouse of the Eif2b5 gene may represent a model for vanishing white matter disease 30 , hence showing a crucial role of this gene in some brain disorders. A long intergenic noncoding RNA is also included in this DNA methylation signature.…”

Section: Discussionmentioning

confidence: 99%

A Dna Methylation Signature Discriminates Between Excellent and Non-Response to Lithium in Patients With Bipolar Disorder Type 1

Lejeune

Bellivier

Étain

2021

Biological Psychiatry

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Lithium (Li) is the cornerstone maintenance treatment for bipolar disorders (BD), but response rates are highly variable. To date, no clinical or biological marker is available to reliably define eligibility criteria for a maintenance treatment with Li. We examined whether the prophylactic response to Li (assessed retrospectively) is associated with distinct blood DNA methylation profiles. Bisulfite-treated total blood DNA samples from individuals with BD type 1 (15 excellent-responders (LiERs) versus 11 non-responders (LinRs)) were used for targeted enrichment of cpG rich genomic regions followed by high-resolution next-generation sequencing to identify differentially methylated regions (DMRs). After controlling for potential confounders we identified 111 DMRs that significantly differ between LiERs and LiNRs with a significant enrichment in neuronal cell components. Logistic regression and receiver operating curves identified a combination of 7 DMRs with a good discriminatory power for response to Li (Area Under the Curve 0.806). Annotated genes associated with these DMRs include Eukaryotic Translation Initiation Factor 2B Subunit Epsilon (EIF2B5), Von Willebrand factor A Domain Containing 5B2 (VWA5B2), Ral GTPase Activating Protein Catalytic Alpha Subunit 1 (RALGAPA1). Although preliminary and deserving replication, these results suggest that biomarkers of response to Li may be identified through peripheral epigenetic measures.An early age at onset, a high rate of mood recurrences, the associated medical health and psychosocial burdens make bipolar disorder (BD) one of the leading causes of disability in the young population 1,2 . Consensus conferences and experts' guidelines recommend lithium (Li) as a first-line prophylactic treatment for BD 3 . Indeed, Li has proven its efficacy for treating acute manic episodes 4 , for preventing mood relapses of any polarity 5,6 , and also for preventing suicidal behaviors 5 .Predicting response to Li in BD is crucial to move towards a more personalized medicine 7 . Indeed, not all patients receiving Li for at least two cumulative years of treatment will display improvement in the frequency and/ or severity of mood recurrences. In individuals with BD who received Li, three subpopulations (full or excellent responders, partial responders and non-responders) have been repeatedly identified, with around one third of the patients belonging to each group [8][9][10] .Considerable research effort has been dedicated to the identification of clinical predictors of a 'good response' to Li, however no definite eligibility criteria for Li treatment has been identified 11 . For example, Hui and colleagues used a meta-analytic approach to suggest six predictors of good response to Li: mania-depression-interval sequence, absence of rapid cycling, absence of psychotic symptoms, family history of bipolar disorder, shorter

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Glial pathology in a novel spontaneous mutant mouse of the Eif2b5 gene: a vanishing white matter disease model

Cited by 19 publications

References 58 publications

Isocaloric low protein diet in a mouse model for vanishing white matter does not impact ISR deregulation in brain, but reveals ISR deregulation in liver

Isocaloric low protein diet in a mouse model for vanishing white matter does not impact ISR deregulation in brain, but reveals ISR deregulation in liver

Foetal onset of EIF2B related disorder in two siblings: cerebellar hypoplasia with absent Bergmann glia and severe hypomyelination

A Dna Methylation Signature Discriminates Between Excellent and Non-Response to Lithium in Patients With Bipolar Disorder Type 1

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