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

Neurobiology of Disease

Mònica Aguilera¹  Neus Prats²  Olga Varea³  Jordi Duran³  Joan J. Guinovart³ 

[1] Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid 28029, Spain;Corresponding authors at: Institute for Research in Biomedicine (IRB Barcelona), C/Baldiri i Reixac 10-12, 08028 Barcelona, Spain.;Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona 08028, Spain;

关键词: Lafora disease;    Glycogen;    Brain aggregates;    Glycogen synthase;    Astrogliosis;    Neuroinflammation;   

DOI  :  

来源: DOAJ

【 摘 要 】

Abstract.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.

【 授权许可】

Unknown