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

Abstract

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 (αDG) 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 αDG glycosylation and abnormal radial glial (RG) fiber migration. The basic polycyclic compound Mannan-007 (Mn007) restored αDG 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 αDG O-mannosyl glycans for normal RG fiber architecture and proper neuronal migration in corticogenesis.

• Authors: Mariko Taniguchi-Ikeda, Michiyo Koyanagi-Aoi, Tatsuo Maruyama, Toru Takaori, Akiko Hosoya, Hiroyuki Tezuka, Shotaro Nagase, Takuma Ishihara, Taisuke Kadoshima, Keiko Muguruma, Keiko Ishigaki, Hidetoshi Sakurai, Akira Mizoguchi, Bennett G Novitch, Tatsushi Toda, Momoko Watanabe, Takashi Aoi
• Journal: iScience (iScience) Vol. 24 Issue 10 Pg. 103140 (Oct 22 2021) ISSN: 2589-0042 [Electronic] United States
• PMID: 34632335 (Publication Type: Journal Article)
• Copyright: © 2021 The Author(s).