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Towards the understanding of the molecular basis of epilepsy in Lafora disease

AuthorsMuñoz-Ballester, Carmen ; Viana, Rosa ; Heredia, Miguel ; López-González, Irene; Ferrer, lsidre; Sanz, Pascual
Issue Date24-Mar-2016
Citation2nd Biennial International Lafora Workshop (2016)
AbstractLafora disease (LD, OMIM 254780) is a fatal rare disorder characterized by epilepsy and neurodegeneration. Although in recent years a lot of information has been gained on the molecular basis of the neurodegeneration that accompanies LD, the molecular basis of epilepsy is poorly understood. Here, we present evidence indicating that the homeostasis of the astrocytic glutamate transporter GL T-1 (EAAT2) is compromised in both mouse models of LD (Epm2a-/- and Epm2b-l-) . Our results indicate that primary astrocytes from LD mice have reduced capacity of glutamate transport, probably because they present a reduction in the levels of the glutamate transporter at the plasma membrane. On the other hand, the overexpression in cellular models of laforin and malin, the two proteins related to LD, results in an accumulation of GLT-1 (EAAT2) at the plasma membrane and in a severe reduction of the ubiquitination of the transporter. All these results suggest that the laforin/malin complex regulates the endocytic recycling of the GL T -1 (EAA T2) transporter. Since, defects in the function of this transporter lead to excitotoxicity and epilepsy, we suggest that the epilepsy that accompanies LD could be due, at least in part, to deficiencies in the function of the GL T -1 (EAA T2) transporter. Since astrocyte dysfunction is accompanied by a pro-inflammatory response, we analyzed the appearance of inflammatory markers in LD mice with disease progression. Increased numbers of reactive astrocytes (expressing the GFAP marker) and microglia (expressing the lba1 marker) together with increased expression of genes encoding cytokines and mediators of the inflammatory response occurs in both LD mouse lines, although being the inflammatory response more severe in Epm2b-l- mice. This is accompanied by increased protein levels of IL 1-13, IL6, TNFa and Cox2, particularly in Epm2b-lmice. The severity of inflammatory changes correlates with more severe clinical symptoms previously described in Epm2b-l- mice. These findings show for the first time increased innate inflammatory responses in LD, which increases with disease progression, pointing to the possibility of using anti-inflammatory agents to mitigate the degenerative process in LD. In summary, our results indicate a critical role of astrocyte function in Lafora disease.
DescriptionConferencia invitada impartida por el Dr. Pascual Sanz en: 2nd Biennial International Lafora Workshop. La Jolla, California, 23-24 de junio de 2016.
Appears in Collections:(IBV) Comunicaciones congresos
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