Intermediate filament dysregulation and astrocytopathy in the human disease model of <i>KLHL16</i> mutation in giant axonal neuropathy (GAN).

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 astrocyte involvement in GAN. To study the underlying mechanisms, we reprogrammed skin fibroblasts from seven GAN patients carrying different KLHL16 mutations to iPSCs. Isogenic controls with restored IF phenotypes were derived via CRISPR/Cas9 editing of one patient carrying a homozygous missense mutation (G332R). Neural progenitor cells (NPCs), astrocytes, and brain organoids were generated through directed differentiation. All GAN iPSC lines were deficient for gigaxon

SUBMITTER: Battaglia R 

PROVIDER: S-EPMC10054982 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature