Optineurin pathology in the spinal cord of amyotrophic lateral sclerosis/parkinsonism-dementia complex patients in Kii Peninsula, Japan

VWM is one of the most prevalent leukodystrophies with unique clinical, pathological and molecular features. It mostly affects children, but may develop at all ages, from birth to senescence. It is dominated by cerebellar ataxia and susceptible to stresses that act as factors provoking disease onset or episodes of rapid neurological deterioration possibly leading to death. VWM is caused by mutations in any of the genes encoding the five subunits of the eukaryotic translation initiation factor 2B (eIF2B). Although eIF2B is ubiquitously expressed, VWM primarily manifests as a leukodystrophy with increasing white matter rarefaction and cystic degeneration, meager astrogliosis with no glial scarring and dysmorphic immature astrocytes and increased numbers of oligodendrocyte progenitor cells that are restrained from maturing into myelin-forming cells. Recent findings point to a central role for astrocytes in driving the brain pathology, with secondary effects on both oligodendroglia and axons. In this, VWM belongs to the growing group of astrocytopathies, in which loss of essential astrocytic functions and gain of detrimental functions drive degeneration of the white matter. Additional disease mechanisms include activation of the unfolded protein response with constitutive predisposition to cellular stress, failure of astrocyte-microglia crosstalk and possibly secondary effects on the oxidative phosphorylation. VWM involves a translation initiation factor. The group of leukodystrophies due to defects in mRNA translation is also growing, suggesting that this may be a common disease mechanism. The combination of all these features makes VWM an intriguing natural model to understand the biology and pathology of the white matter.