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• W2565777350 abstract "Lafora disease (LD) is a fatal neurodegenerative epilepsy, characterized by the presence of intracellular polyglucosan inclusions in many tissues called Lafora bodies (LBs). LD is caused by loss-of-function mutations in the genes encoding laforin or malin. Previous studies suggested a role of these proteins in the regulation of glycogen synthesis, glycogen dephosphorylation and the modulation of the intracellular proteolytic system. However, the contribution of each one of these processes to LD pathogenesis is unclear. Laforin-deficient (Epm2a-/-) mice recapitulate the most salient traits of the disease: LBs formation and neurological alterations. In this thesis, we have characterized malin-deficient (Epm2b-/-) mice as a suitable model to study LD and understand some of its traits such as the mechanisms of LB formation in the brain. The presence of impaired macroautophagy, possibly regulated by mTOR pathway, previous to the appearance of LBs and in both LD mouse models, suggests that the laforin-malin complex modulates autophagy and plays a primary role in LD pathology. However, we treated with Rapamycin, an mTOR inhibitor, Epm2a-/- and Epm2b-/- mice before the appearance of LBs and mice do not ameliorate, rather they form a large number of LBs, which are sparsely observed also in Rapamicin treated wild type mice. Taking advantage of two Epm2a-/- mouse lines over-expressing a wild-type or phosphatase-deficient form of laforin we have demonstrated that both forms can prevent the formation of LBs, highlighting that the critical point of polyglucosan accumulation is the control of glycogen synthesis through intracellular proteolytic systems mediated by the laforin-malin complex, and not glycogen dephosphorylation mediated by laforin. To determine how deficiency of laforin and malin influence neuronal function, we have first explored if inhibitory neurons are a specific target of LD pathology, finding no evidence for this possibility. By analyzing morpho-physiological characteristic of two weeks old hippocampal neurons we have demonstrated the presence of morphological and electrophysiologycal alterations that precede the appearance of LBs, which might be linked to the synaptic localization of laforin and its protein levels. Altogether the data presented in this thesis, provide new insights in the pathogenesis of the disease, illustrating that several alterations precedes the formation of LBs and providing an explanation for the epileptic activity of LD. Furthermore, on the basis of our results we propose that laforin-malin complex dysfunction is the primary cause of LD pathology, leading to a final consequence of laforin deficiency, which affects synaptic transmission promoting epilepsy." @default.
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• W2565777350 date "2015-01-01" @default.
• W2565777350 modified "2023-09-23" @default.
• W2565777350 title "Brain alterations in lafora disease mouse models" @default.
• W2565777350 hasPublicationYear "2015" @default.
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