Analysis on the glycan structure of alpha-dystroglycan and the therapeutic approach for Fukuyama-congenital muscular dystrophy

2014 Fiscal Year Final Research Report

• Project/Area Number: 24790884
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Neurology
• Research Institution: Kobe University
• Principal Investigator: KUGA Atsushi 神戸大学, 医学部附属病院, 助教 (30608790)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Keywords: dystroglycan / fukutin / FKRP / リビトール

Outline of Final Research Achievements

Aberrant glycosylation of α-dystroglycan (α-DG) causes muscular dystrophy and lissencephaly, which we call α-dystroglycanopathies. Here we identified the previously unknown glycan unit ribitol 5-phosphate (Rbo5P) in α-DG. Rbo5P forms a tandem repeat and functions as a scaffold for the formation of the ligand-binding moiety. We found the enzyme activities of three major α-dystroglycanopathy-causing proteins to be involved in the synthesis of tandem Rbo5P. Isoprenoid synthase domain-containing (ISPD) is cytidine diphosphate ribitol (CDP-Rbo) synthase. Fukutin and fukutin-related protein are Rbo5P transferases that use CDP-Rbo. Supplementation of CDP-Rbo to ISPD-deficient cells restored α-DG glycosylation. These findings establish the molecular basis of mammalian Rbo5P glycosylation, and reveal the pathogenesis and therapeutic strategies of α-DG-associated diseases.

Free Research Field

筋ジストロフィーの分子病態