Proteosome inhibitor repurposing rescues hypomyelination in HIKESHI-associated Leukodystrophy

HIKESHI-associated leukodystrophy (HAL) is a lethal genetic neurological condition with most patients dying in childhood. HAL is caused by homozygous mutations in the HIKESHI gene leading to protein loss. HIKESHI serves as a nuclear import carrier for chaperone HSP70 during heat shock response (HSR). As the primary abnormalities are related to white matter, we geneated iPSCs from affected homozygous HAL patients, non-symptomatic heterozygous first-degree relatives, and healthy unrelated individuals. iPSCs were differentiated into oligodendrocytes, followed by immunofluorescent staining and various assays. Bulk RNASeq revealed various upregulated and downregulated genes during oligodendrocyte development. Immunofluorescence indicates HSP70 and other proteins displayed altered nuclear localization in HIKESHI homozygous cells. Homozygous cells also had much fewer Olig2+ cells, aberrant myelination, and misshapen cells. We conclude that loss of HIKESHI results in dysfunction of oligodendrocyte development and function.