Vanishing white matter (VWM) is a fatal, stress-sensitive leukodystrophy that mainly affects children and is currently without treatment. VWM is caused by recessive mutations in eukaryotic initiation factor 2B (eIF2B) that is crucial for initiation of mRNA translation and its regulation during the integrated stress response (ISR). Mutations reduce eIF2B activity. VWM pathomechanisms remain unclear. In contrast with the housekeeping function of eIF2B, astrocytes are selectively affected in VWM. One study objective was to test our hypothesis that in the brain translation of specific mRNAs is altered by eIF2B mutations, impacting primarily astrocytes. The second objective was to investigate whether modulation of eIF2B activity could ameliorate this altered translation and improve the disease. Mice with biallelic missense mutations in eIF2B that recapitulate human VWM were used to screen for mRNAs with altered translation in brain using polysomal profiling. Findings were verified in brain tissue from VWM patients using qPCR and immunohistochemistry. The compound ISRIB (for "ISR inhibitor") was administered to VWM mice to increase eIF2B activity. Its effect on translation, neuropathology, and clinical signs was assessed. In brains o...Continue Reading
Increased cerebrospinal fluid glycine: a biochemical marker for a leukoencephalopathy with vanishing white matter
Redox state is a central modulator of the balance between self-renewal and differentiation in a dividing glial precursor cell
Feedback inhibition of the unfolded protein response by GADD34-mediated dephosphorylation of eIF2alpha
Subunits of the translation initiation factor eIF2B are mutant in leukoencephalopathy with vanishing white matter
Mutations in each of the five subunits of translation initiation factor eIF2B can cause leukoencephalopathy with vanishing white matter
XBP-1 regulates a subset of endoplasmic reticulum resident chaperone genes in the unfolded protein response.
Inhibition of a constitutive translation initiation factor 2alpha phosphatase, CReP, promotes survival of stressed cells
Mutations linked to leukoencephalopathy with vanishing white matter impair the function of the eukaryotic initiation factor 2B complex in diverse ways.
CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum
Glia-specific activation of all pathways of the unfolded protein response in vanishing white matter disease
ATF4-mediated induction of 4E-BP1 contributes to pancreatic beta cell survival under endoplasmic reticulum stress
Postnatal deamidation of 4E-BP2 in brain enhances its association with raptor and alters kinetics of excitatory synaptic transmission.
Severity of vanishing white matter disease does not correlate with deficits in eIF2B activity or the integrity of eIF2B complexes.
Integrated stress response modulates cellular redox state via induction of cystathionine γ-lyase: cross-talk between integrated stress response and thiol metabolism.
Identification of residues that underpin interactions within the eukaryotic initiation factor (eIF2) 2B complex.
Partial restoration of protein synthesis rates by the small molecule ISRIB prevents neurodegeneration without pancreatic toxicity
Stress responses. Mutations in a translation initiation factor identify the target of a memory-enhancing compound
Pharmacological dimerization and activation of the exchange factor eIF2B antagonizes the integrated stress response
Bergmann glia translocation: a new disease marker for vanishing white matter identifies therapeutic effects of Guanabenz treatment
The small molecule ISRIB rescues the stability and activity of Vanishing White Matter Disease eIF2B mutant complexes
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.
ISRIB Blunts the Integrated Stress Response by Allosterically Antagonising the Inhibitory Effect of Phosphorylated eIF2 on eIF2B.
Translation initiation factor eIF2Bε promotes Wnt-mediated clonogenicity and global translation in intestinal epithelial cells.
Astrocytes are glial cells that support the blood-brain barrier, facilitate neurotransmission, provide nutrients to neurons, and help repair damaged nervous tissues. Here is the latest research.