Lithium exacerbates Lafora body formation in the Epm2aLafora disease mouse model.

Abstract

Lafora disease (LD) is a fatal neurodegenerative epilepsy of teenagers due to accumulations of overlong-branched glycogen (Lafora bodies, LBs) and caused by deficient laforin or its interacting partner malin. While how the laforin-malin complex regulates glycogen chain lengths is unknown, it is known that downregulating the glycogen chain-elongating enzyme glycogen synthase prevents LB formation. Lithium is a longstanding treatment for neuropsychiatric diseases. Lithium was recently shown to lead to glycogen synthase phosphorylation (i.e. inhibition) in rat brains through an unknown pathway. We tested whether lithium can prevent LB formation in laforin-deficient LD mice. We found that in these mice lithium leads to glycogen synthase dephosphorylation (i.e. activation), and increased LBs in hearts of 100% and brains of 40% of treated mice. The latter were all sickly compared to the 60% in whose brains LBs did not increase. These results are generally cautionary regarding therapeutic translatability from rodents to humans where basic mechanisms are unknown. Increased LB formation only in frail mice suggests existence of self-perpetuating processes in LD. Finally, lithium clearly influences glycogen metabolism with outcomes similar to disturbances of the laforin-malin complex. Understanding lithium's action in glycogen metabolism may aid the understanding of the mechanisms of laforin-malin and LD.