Inhibiting glycogen synthesis prevents Lafora disease in a mouse model

Area of Science:

• Neuroscience
• Biochemistry
• Genetics

Background:

• Lafora disease (LD) is a fatal, progressive myoclonus epilepsy.
• Neuropathology involves Lafora bodies (LBs), aggregates of abnormal glycogen and proteins, and neurodegeneration.
• The role of LBs in pathogenesis and the potential for preventing LB formation by inhibiting glycogen synthesis were uncertain.

Purpose of the Study:

• To investigate whether inhibiting brain glycogen synthesis could prevent Lafora body formation and associated pathology in a mouse model of Lafora disease.
• To determine if Lafora bodies are pathogenic and contribute to neurodegeneration and epilepsy in LD.

Main Methods:

• Genetic elimination of brain glycogen synthesis in Lafora disease mice.
• Long-term monitoring for Lafora body formation, neurodegeneration, and seizure susceptibility.

Main Results:

• Complete prevention of Lafora body formation was achieved in mice with eliminated brain glycogen synthesis.
• Neurodegeneration and seizure susceptibility were long-term prevented.
• The study provides strong evidence that glycogen synthesis is essential for Lafora body formation.

Conclusions:

• Lafora bodies are pathogenic and their formation is dependent on glycogen synthesis.
• Inhibiting glycogen synthesis is a viable therapeutic strategy for Lafora disease.
• This research opens a therapeutic window for Lafora disease using glycogen synthesis inhibitors.