Mitochondrial malfunction in vanishing white matter disease： a disease of the cytosolic translation machinery

Vanishing white matter （VWM） disease - a disease of the cytosolic translation machinery： VWM is a recessive genet- ic neurodegenerative disease caused by mutations in any of the five genes encoding the subunits of translation initiation factor 2B （eIF2B） （Leegwater et al., 2001; OMIM 306896）.

Different Eukaryotic Initiation Factor 2Be Mutations Lead to Various Degrees of Intolerance to the Stress of Endoplasmic Reticulum in Oligodendrocytes

Vanishing white matter disease （VWM）, a human atitosomal recessive inherited leukoencephalopathy, is due to mutations in eukaryotic initiation factor 2B （elF2B）. elF2B is responsible for tile initiation of protein synthesis by its guanine nucleotide exchange lhctor （GEF） activity. Mutations ofelF2B impair GEF activity at different degree. Previous studies implied improperly activated unlblded protein response （UPR） and endoplasmic reticulum stress （ERS） participated in the pathogenesis ofVWM. Autophagy relieves endoplasmic reticulum load by eliminating the unfolded protein. It is still unknown the effects of genotypes on the pathogenesis. In this work, UPR and autophagy flux were analyzed with different mutational types. Methods： ERS tolerance, reflected by apoptosis and cell viability, was detected in human oligodendrocyte cell line transfected with the wild type, or different mutations of p. Argl 13 His, p. Arg269＊ or p. Ser610-Asp613del in el F2 Be. A representative U PR-PERK component of activating transcription lhctor 4 （ATF4） was measured under the basal condition and ERS induction. Autophagy was analyzed the flux in the presence of lysosomal inhibitors. Results： The degree of ERS tolerance varied in different genotypes. The truncated or deletion mutant showed prominent apoptosis cell viability declination after ERS induction. The most seriously damaged GEF activity ofp. Arg269＊ group underwent spontaneous apoptosis. The truncated or deletion mutant showed elevated ATF4 under basal as well as ERS condition. Decreased expression of LC3-1 and LC3-11 in the mutants reflected an impaired autophagy flux, which was more obvious in the truncated or deletion mutants alter ERS induction. Conclusions： GEF activities in dilt;erent genotypes could influence the cell ERS tolerance as well as compensatory pathways of UPR and autophagy. Oligodendrocytes with truncated or deletion inutants showed less tolerable to ERS.