Endocytosis of the glutamate transporter 1 is regulated by laforin and malin: Implications in Lafora disease

Abstract

Lafora disease (LD) is a fatal rare type of progressive myoclonus epilepsy that appears during early adolescence. The disease is caused by mutations in EPM2A or EPM2B genes, which encode laforin, a glucan phosphatase, and malin, an E3‐ubiquitin ligase, respectively. Although the exact roles of laforin and malin are still not well understood, it is known that they work as a complex in which laforin recruits targets that will be ubiquitinated by malin. Recently, we suggested that the type of epilepsy that accompanies LD could be due to deficiencies in the function of the astrocytic glutamate transporter GLT‐1. We described that astrocytes from LD mouse models presented decreased levels of GLT‐1 at the plasma membrane, leading to increased levels of glutamate in the brain parenchyma. In this work, we present evidence indicating that in the absence of a functional laforin/malin complex (as in LD cellular models) there is an alteration in the ubiquitination of GLT‐1, which could be the cause of the reduction in the levels of GLT‐1 at the plasma membrane. On the contrary, overexpression of the laforin/malin complex promotes the retention of GLT‐1 at the plasma membrane. This retention may be due to the direct ubiquitination of GLT‐1 and/or to an opposite effect of this complex on the dynamics of the Nedd4.2‐mediated endocytosis of the transporter. This work, therefore, presents new pieces of evidence on the regulation of GLT‐1 by the laforin/malin complex, highlighting its value as a therapeutic target for the amelioration of the type of epilepsy that accompanies LD.

Pharmacological Modulation of Glutamatergic and Neuroinflammatory Pathways in a Lafora Disease Mouse Model

“…Successfully, Muñoz-Ballester et al [ 23 ] unravelled a decreased level of glutamate transporter GLT-1 at the plasma membrane of LD astrocytes, which might underlie the in vivo glutamate clearance defects present in LD mouse models [ 24 ]. Furthermore, Perez-Jimenez et al [ 25 ] confirmed that such defective alterations are related to insufficient ubiquitination of GLT-1 due to the absence of a functional laforin/malin complex. On the basis of these strong data, it became clear that an altered excitatory glutamatergic system might be behind the sensitivity to convulsant agents observed in LD mouse models [ 26 , 27 ].…”

Glial Contributions to Lafora Disease: A Systematic Review

“…First, impaired K + and glutamate clearance, as seen above, can lead to neuronal hyperexcitability and contribute to epileptogenesis. In this regard, in addition to the aforementioned data on EAAT2 [ 52 , 53 , 54 ], we recently observed the upregulation of the astrocytic Kir4.1 channel in a new laforin-deficient zebrafish model [ 14 ]. The downregulation of this channel has generally been described in inflammatory states, but impaired function of Kir4.1 has also been associated with autism–epilepsy phenotypes in humans [ 127 ], and we therefore cannot exclude a possible role for it in the epileptic phenotype observed in epm2a KO larvae.…”

“…Five additional studies were selected by checking the references of the identified relevant papers. A total of 35 studies were then identified for inclusion in the current review [ 10 , 12 , 14 , 18 , 21 , 22 , 23 , 38 , 39 , 40 , 41 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 ].…”

“…Second, inflammatory cytokines (e.g., TNFα and IL-6) released by proinflammatory glial cells reduce glutamate uptake by EAAT2 transporters and promote its astrocytic release [ 96 , 97 , 98 ]. A third mechanism demonstrated in cellular [ 52 ] and mouse models [ 53 ] of LD is the functional reduction in the astrocytic EEAT2 transporter [ 52 , 53 ] linked to its altered ubiquitination and recycling due to the deficiency of the laforin/malin complex [ 54 ].…”

Pharmacological modulation of glutamatergic and neuroinflammatory pathways in a Lafora disease mouse model

“…Successfully, Muñoz-Ballester et al [23] unraveled a decreased level of glutamate transporter GLT-1 at the plasma membrane of LD astrocytes, which might underlie the in vivo glutamate clearance defects present in LD mouse models [24]. Furthermore, Perez-Jimenez et al [25] con rmed that such defective alterations are related to insu cient ubiquitination of GLT-1 due to the absence of a functional laforin/malin complex. On the strength of these data, it became clear that an altered excitatory glutamatergic system might be behind the sensitivity to convulsant agents observed in LD mouse models [26], [27].…”