Link to bioRxiv paper:
http://biorxiv.org/cgi/content/short/2023.03.13.532440v1?rss=1

Authors: Battaglia, R., Faridounnia, M., Beltran, A., Robinson, J., Kinghorn, K., Ezzell, J. A., Bharucha-Goebel, D., Bonnemann, C., Hooper, J. E., Opal, P., Bouldin, T. W., Armao, D., Snider, N.

Abstract:
Giant Axonal Neuropathy (GAN) is a pediatric neurodegenerative disease caused by KLHL16 mutations. KLHL16 encodes gigaxonin, a regulator of intermediate filament (IF) protein turnover. Previous neuropathological studies and our own examination of postmortem GAN brain tissue in the current study revealed significant involvement of astrocytes in GAN. To study the underlying cellular mechanisms, we generated human models of GAN using induced pluripotent stem cells (iPSCs). Skin fibroblasts from seven GAN patients carrying different KLHL16 mutations were reprogrammed to iPSCs, and isogenic controls were derived via CRISPR/Cas9 editing. Neural progenitor cells (NPCs), astrocytes, and brain organoids were generated through directed differentiation. All GAN iPSC lines were deficient for gigaxonin, which was restored in the isogenic clones. While GAN iPSCs displayed normal organization of lamin B1 and keratin IFs, they exhibited patient-specific increased expression and perinuclear bundling of vimentin. Nestin IF morphology was unaffected, but fewer nestin-positive cells were present in GAN NPCs compared to controls. The most dramatic phenotypes were observed in GAN iPSC-astrocytes and brain organoids, which displayed dense perinuclear IF accumulations and abnormal nuclear morphology. GFAP oligomerization and perinuclear aggregation were strongly potentiated in the presence of vimentin, and GAN cells with large perinuclear vimentin aggregates accumulated nuclear KLHL16 mRNA. As an early effector of KLHL16 mutations, vimentin may be a potential target in GAN.

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