Elucidation of pathomecanism for Fukuyama muscular dystrophy and dystroglycanopathy and their drug developmen

2017 Fiscal Year Final Research Report

• Project/Area Number: 26253057
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Neurology
• Research Institution: Kobe University
• Principal Investigator: Toda Tatsusi 神戸大学, 医学研究科, 教授 (30262025)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Keywords: 福山型筋ジストロフィー / ジストログリパノカチー / リビトールリン酸 / フクチン / アンチセンス治療

Outline of Final Research Achievements

We re-designed AONs precisely around the splice sites and assessed the efficacy for exon trap inhibition of these AONs in Fukuyama CMD patient cells and model mice. We finally selected one best candidate AON. We demonstrated that fukutin is required for LARGE-dependent rescue of α-DG glycosylation. We further identified the previously unknown glycan unit ribitol 5-phosphate (Rbo5P), a phosphoric ester of pentose alcohol, as a tandem repeat that functions as a scaffold for the formation of the ligand-binding moiety of α-DG. We determined the enzyme activities of three major α-DGpathy-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. We also indicate that spatiotemporal persistence of functionally glycosylated dystroglycan may be crucial for brain development.

Free Research Field

医歯薬学