Suppression of glycogen synthesis as a treatment for Lafora disease: Establishing the window of opportunity
| Autor: | Jordi Duran, Neus Prats, Joan J. Guinovart, Mònica Aguilera, Olga Varea |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Astrogliosis Lafora disease Article Proinflammatory cytokine lcsh:RC321-571 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine Neuroinflammation medicine Animals Glycogen synthase Muscle Skeletal lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry Mice Knockout Brain aggregates Epilepsy Microglia Glycogen biology Skeletal muscle Brain medicine.disease Cell biology Mice Inbred C57BL Epilèpsia Glicogen Disease Models Animal 030104 developmental biology medicine.anatomical_structure Neurology chemistry biology.protein 030217 neurology & neurosurgery |
| Zdroj: | Neurobiology of Disease, Vol 147, Iss, Pp 105173-(2021) Dipòsit Digital de la UB Universidad de Barcelona Neurobiol Dis |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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