Suppression of glycogen synthesis as a treatment for Lafora disease: Establishing the window of opportunity

• Published in: Neurobiology of disease Vol. 147; p. 105173
• Main Authors: Varea, Olga, Duran, Jordi, Aguilera, Mònica, Prats, Neus, Guinovart, Joan J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.01.2021; Elsevier
• Subjects: Animals; Astrogliosis; Brain - pathology; Brain aggregates; Disease Models, Animal; Glycogen; Glycogen - biosynthesis; Glycogen synthase; Glycogen Synthase - genetics; Glycogen Synthase - metabolism; Lafora disease; Lafora Disease - pathology; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle, Skeletal - pathology; Neuroinflammation; Astrogliosis; Neuroinflammation; Glycogen; Glycogen synthase; Lafora disease; Brain aggregates
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1016/j.nbd.2020.105173

Lafora disease (LD) is a fatal adolescence-onset neurodegenerative condition. The hallmark of LD is the accumulation of aberrant glycogen aggregates called Lafora bodies (LBs) in the brain and other tissues. Impeding glycogen synthesis from early embryonic stages by genetic suppression of glycogen synthase (MGS) in an animal model of LD prevents LB formation and ultimately the pathological manifestations of LD thereby indicating that LBs are responsible for the pathophysiology of the disease. However, it is not clear whether eliminating glycogen synthesis in an adult animal after LBs have already formed would halt or reverse the progression of LD. Herein we generated a mouse model of LD with inducible MGS suppression. We evaluated the effect of MGS suppression at different time points on LB accumulation as well as on the appearance of neuroinflammation, a pathologic trait of LD models. In the skeletal muscle, MGS suppression in adult LD mice blocked the formation of new LBs and reduced the number of glycogen aggregates. In the brain, early but not late MGS suppression halted the accumulation of LBs. However, the neuroinflammatory response was still present, as shown by the levels of reactive astrocytes, microglia and inflammatory cytokines. Our results confirm that MGS as a promising therapeutic target for LD and highlight the importance of an early diagnosis for effective treatment of the disease. •Early suppression of glycogen synthase arrests the accumulation of Lafora bodies in the brain of Lafora disease model.•Early suppression of glycogen synthase greatly reduces Lafora bodies in muscle of Lafora disease model.•Glycogen synthase suppression at the time points tested is insufficient to prevent the appearance of neuroinflammation.•·An early Lafora disease-genetic diagnosis is crucial for the efficiency of glycogen synthase-based therapeutic approaches.