title: Homeostasis of the astrocytic glutamate transporter GLT-1 is altered in mouse models of Lafora disease.
abstract: Lafora 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 glutamate transporter GLT-1 (EAAT2) is compromised in mouse models of LD. 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 slows down the endocytic recycling of the GLT-1 (EAAT2) 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 GLT-1 (EAAT2) transporter.
authors.affiliation: Instituto de Biomedicina de Valencia (CSIC) and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Valencia, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Muñoz-Ballester
authors.affiliation: Instituto de Biomedicina de Valencia (CSIC) and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Valencia, Spain.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Berthier
authors.affiliation: Instituto de Biomedicina de Valencia (CSIC) and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Valencia, Spain.
authors.forename: Rosa
authors.initials: R
authors.lastname: Viana
authors.affiliation: Instituto de Biomedicina de Valencia (CSIC) and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Valencia, Spain. Electronic address: sanz@ibv.csic.es.
authors.forename: Pascual
authors.initials: P
authors.lastname: Sanz
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology; D002460:Cell Line; D002478:Cells, Cultured; D004195:Disease Models, Animal; D054637:Dual-Specificity Phosphatases / Q000032:analysis / Q000378:metabolism; D004705:Endocytosis; D027342:Excitatory Amino Acid Transporter 2 / Q000032:analysis / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D020192:Lafora Disease / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D054558:Protein Tyrosine Phosphatases, Non-Receptor; D054875:Ubiquitination
chemical_list: D027342:Excitatory Amino Acid Transporter 2; C493396:Slc1a2 protein, mouse; D054637:Dual-Specificity Phosphatases; C491989:Epm2a protein, mouse; D054558:Protein Tyrosine Phosphatases, Non-Receptor
keywords: EAAT2; Endocytosis; Epilepsy; GLT-1; Glutamate transport; Lafora disease; Protein recycling; Ubiquitination