Restoration of the defect in radial glial fiber migration and cortical plate organization in a brain organoid model of Fukuyama muscular dystrophy

Fukuyama congenital muscular dystrophy (FCMD) is a severe, intractable genetic disease that affects the skeletal muscle, eyes, and brain and is attributed to a defect in alpha dystroglycan (alpha DG) O-mannosyl glycosylation. We previously established disease models of FCMD; however, they did not fully recapitulate the phenotypes observed in human patients. In this study, we generated induced pluripotent stem cells (iPSCs) from a human FCMD patient and differentiated these cells into three-dimensional brain organoids and skeletal muscle. The brain organoids successfully mimicked patient phenotypes not reliably reproduced by existing models, including decreased alpha DG glycosylation and abnormal radial glial (RG) fiber migration. The basic polycyclic compound Mannan-007 (Mn007) restored alpha DG glycosylation in the brain and muscle models tested and partially rescued the abnormal RG fiber migration observed in cortical organoids. Therefore, our study underscores the importance of alpha DG O-mannosyl glycans for normal RG fiber architecture and proper neuronal migration in corticogenesis.

Automated summary

This study successfully modeled the phenotypes of Fukuyama congenital muscular dystrophy (FCMD) patients by using induced pluripotent stem cells (iPSCs) and differentiated brain organoids and skeletal muscle. It found the importance of alpha DG O-mannosyl glycans for normal RG fiber architecture and proper neuronal migration in corticogenesis. Additionally, the compound Mannan-007 (Mn007) showed promising results in restoring alpha DG glycosylation and partially rescuing abnormal RG fiber migration.