Poor cerebral inflammatory response in eIF2B knock-in mice : implications for the aetiology of vanishing white matter disease
BACKGROUND: Mutations in any of the five subunits of eukaryotic translation initiation factor 2B (eIF2B) can lead to an inherited chronic-progressive fatal brain disease of unknown aetiology termed leucoencephalopathy with vanishing white matter (VWM). VWM is one of the most prevalent childhood white matter disorders, which markedly deteriorates after inflammation or exposure to other stressors. eIF2B is a major housekeeping complex that governs the rate of global protein synthesis under normal and stress conditions. A previous study demonstrated that Eif2b5(R132H/R132H) mice suffer delayed white matter development and fail to recover from cuprizone-induced demyelination, although eIF2B enzymatic activity in the mutant brain is reduced by merely 20%.
PRINCIPAL FINDINGS: Poor astrogliosis was observed in Eif2b5(R132H/R132H) mice brain in response to systemic stress induced by peripheral injections of lipopolysaccharide (LPS). Even with normal rates of protein synthesis under normal conditions, primary astrocytes and microglia isolated from mutant brains fail to adequately synthesise and secrete cytokines in response to LPS treatment despite proper induction of cytokine mRNAs.
CONCLUSIONS: The mild reduction in eIF2B activity prevents the appropriate increase in translation rates upon exposure to the inflammatory stressor LPS. The data underscore the importance of fully-functional translation machinery for efficient cerebral inflammatory response upon insults. It highlights the magnitude of proficient translation rates in restoration of brain homeostasis via microglia-astrocyte crosstalk. This study is the first to suggest the involvement of microglia in the pathology of VWM disease. Importantly, it rationalises the deterioration of clinical symptoms upon exposure of VWM patients to physiological stressors and provides possible explanation for their high phenotypic variability.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2012 |
|---|---|
| Erschienen: |
2012 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:7 |
|---|---|
| Enthalten in: |
PloS one - 7(2012), 10 vom: 08., Seite e46715 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Cabilly, Yuval [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
Eukaryotic Initiation Factor-2B |
|---|
| Anmerkungen: |
Date Completed 03.05.2013 Date Revised 21.10.2021 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1371/journal.pone.0046715 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM221743340 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM221743340 | ||
| 003 | DE-627 | ||
| 005 | 20231224052617.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231224s2012 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1371/journal.pone.0046715 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n0739.xml |
| 035 | |a (DE-627)NLM221743340 | ||
| 035 | |a (NLM)23056417 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Cabilly, Yuval |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Poor cerebral inflammatory response in eIF2B knock-in mice |b implications for the aetiology of vanishing white matter disease |
| 264 | 1 | |c 2012 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 03.05.2013 | ||
| 500 | |a Date Revised 21.10.2021 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a BACKGROUND: Mutations in any of the five subunits of eukaryotic translation initiation factor 2B (eIF2B) can lead to an inherited chronic-progressive fatal brain disease of unknown aetiology termed leucoencephalopathy with vanishing white matter (VWM). VWM is one of the most prevalent childhood white matter disorders, which markedly deteriorates after inflammation or exposure to other stressors. eIF2B is a major housekeeping complex that governs the rate of global protein synthesis under normal and stress conditions. A previous study demonstrated that Eif2b5(R132H/R132H) mice suffer delayed white matter development and fail to recover from cuprizone-induced demyelination, although eIF2B enzymatic activity in the mutant brain is reduced by merely 20% | ||
| 520 | |a PRINCIPAL FINDINGS: Poor astrogliosis was observed in Eif2b5(R132H/R132H) mice brain in response to systemic stress induced by peripheral injections of lipopolysaccharide (LPS). Even with normal rates of protein synthesis under normal conditions, primary astrocytes and microglia isolated from mutant brains fail to adequately synthesise and secrete cytokines in response to LPS treatment despite proper induction of cytokine mRNAs | ||
| 520 | |a CONCLUSIONS: The mild reduction in eIF2B activity prevents the appropriate increase in translation rates upon exposure to the inflammatory stressor LPS. The data underscore the importance of fully-functional translation machinery for efficient cerebral inflammatory response upon insults. It highlights the magnitude of proficient translation rates in restoration of brain homeostasis via microglia-astrocyte crosstalk. This study is the first to suggest the involvement of microglia in the pathology of VWM disease. Importantly, it rationalises the deterioration of clinical symptoms upon exposure of VWM patients to physiological stressors and provides possible explanation for their high phenotypic variability | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Eukaryotic Initiation Factor-2B |2 NLM | |
| 650 | 7 | |a Lipopolysaccharides |2 NLM | |
| 700 | 1 | |a Barbi, Mali |e verfasserin |4 aut | |
| 700 | 1 | |a Geva, Michal |e verfasserin |4 aut | |
| 700 | 1 | |a Marom, Liraz |e verfasserin |4 aut | |
| 700 | 1 | |a Chetrit, David |e verfasserin |4 aut | |
| 700 | 1 | |a Ehrlich, Marcelo |e verfasserin |4 aut | |
| 700 | 1 | |a Elroy-Stein, Orna |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t PloS one |d 2006 |g 7(2012), 10 vom: 08., Seite e46715 |w (DE-627)NLM167327399 |x 1932-6203 |7 nnns |
| 773 | 1 | 8 | |g volume:7 |g year:2012 |g number:10 |g day:08 |g pages:e46715 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1371/journal.pone.0046715 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 7 |j 2012 |e 10 |b 08 |h e46715 | ||