A mouse model for eukaryotic translation initiation factor 2B-leucodystrophy reveals abnormal development of brain white matter

Abstract

Eukaryotic translation initiation factor 2B is a major housekeeping complex that governs the rate of global protein synthesis under normal and stress conditions. Mutations in any of its five subunits lead to leucoencephalopathy with vanishing white matter, an inherited chronic-progressive fatal brain disease with unknown aetiology, which is among the most prevalent childhood white matter disorders. We generated the first animal model for the disease by introducing a point mutation into the mouse Eif2b5 gene locus, leading to R132H replacement corresponding to the clinically significant human R136H mutation in the catalytic subunit. In contrast to human patients, mice homozygous for the mutant Eif2b5 allele (Eif2b5(R132H/R132H) mice) enable multiple analyses under a defined genetic background during the pre-symptomatic stages and during recovery from a defined brain insult. Time-course magnetic resonance imaging revealed for the first time the delayed development of the brain white matter due to the mutation. Electron microscopy demonstrated a higher proportion of small-calibre nerve fibres. Immunohistochemistry detected an abnormal abundance of oligodendrocytes and astrocytes in the brain of younger animals, as well as an abnormal level of major myelin proteins. Most importantly, mutant mice failed to recover from cuprizone-induced demyelination, reflecting an increased sensitivity to brain insults. The anomalous development of white matter in Eif2b5(R132H/R132H) mice underscores the importance of tight translational control to normal myelin formation and maintenance.

Astrocytes are central in the pathomechanisms of vanishing white matter

“…VWM mice have a higher proportion of small-caliber axons than do WT animals (present study; ref. 30). Scattered axonal swellings are only detected in the oldest mutants with advanced disease, but the axonal cytoskeleton appears otherwise intact.…”

“…Additional manipulations may force mice to develop a phenotype that more closely matches that of the human disease, but these have the unwanted side effect of influencing the disease mechanisms (49-52). Geva et al (30) previously generated a VWM mouse model by inserting Arg132His into eIF2Bε, a mutation that in the homozygous state in humans is associated with childhood-onset disease and death in adolescence. This mutant mouse had a normal lifespan, subtle motor impairment at most, and white matter abnormalities that only became manifest after experimental demyelination (30,53).…”

“…Geva et al (30) previously generated a VWM mouse model by inserting Arg132His into eIF2Bε, a mutation that in the homozygous state in humans is associated with childhood-onset disease and death in adolescence. This mutant mouse had a normal lifespan, subtle motor impairment at most, and white matter abnormalities that only became manifest after experimental demyelination (30,53). Using transgenic mice that allow activation of PERK specifically in oligodendrocytes, Lin et al (52) concluded that PERK activation in oligodendrocytes plays a cell-autonomous role in VWM pathology.…”

Axonal abnormalities in vanishing white matter

“…Overall, our results indicate that axons and relative myelin sheath thickness are initially normal or close to normal and only secondarily axonal atrophy occurs, dependent on disease severity. Previously, a different Eif2b5 mutant mouse model was reported to display a higher proportion of thin axons in the internal capsule associated with thinner myelin sheaths and a normal G‐ratio at 3 weeks 33. Axonal diameter and myelin sheath thickness at later ages were not reported, but it was demonstrated that in the cerebral peduncle of 15‐month‐old mutants an increased proportion of axons had no or thinner myelin than of wild‐type mice.…”

The Role of NO/cGMP Signaling on Neuroinflammation: A New Therapeutic Opportunity

“…Oligodendrocyte dysfunction and myelin abnormalities are found in a wide variety of neurological diseases and may be involved in the pathophysiology of various diseases, including genetic leukodystrophies [74], schizophrenia and bipolar disorder [75,76], brain injury [77], and endocrine and metabolic abnormalities [78,79] and neurodegenerative conditions such as strokes [80,81], Parkinson's disease [82], Alzheimer's disease [83][84][85], multiple sclerosis [86], and diabetic encephalopathy [87].…”