dc.contributor.author | Kumarasinghe, Lorena | |
dc.contributor.author | García Gimeno, María Adelaida | |
dc.contributor.author | Ramírez Sánchez, Juan Manuel | |
dc.contributor.author | Mayor Martínez, Ugo | |
dc.contributor.author | Zugaza Gurruchaga, José Luis | |
dc.contributor.author | Sanz, Pascual | |
dc.date.accessioned | 2023-02-07T18:01:47Z | |
dc.date.available | 2023-02-07T18:01:47Z | |
dc.date.issued | 2023-01 | |
dc.identifier.citation | Neurobiology of Disease 177 : (2023) // Article ID 105998 | es_ES |
dc.identifier.issn | 1095-953X | |
dc.identifier.uri | http://hdl.handle.net/10810/59711 | |
dc.description.abstract | Laforin and Malin are two proteins that are encoded by the genes EPM2A and EPM2B, respectively. Laforin is a glucan phosphatase and Malin is an E3-ubiquitin ligase, and these two proteins function as a complex. Mutations occurring at the level of one of the two genes lead to the accumulation of an aberrant form of glycogen meant to cluster in polyglucosans that go under the name of Lafora bodies. Individuals affected by the appearance of these polyglucosans, especially at the cerebral level, experience progressive neurodegeneration and several episodes of epilepsy leading to the manifestation of a fatal form of a rare disease called Lafora disease (LD), for which, to date, no treatment is available. Despite the different dysfunctions described for this disease, many molecular aspects still demand elucidation. An effective way to unknot some of the nodes that prevent the achievement of better knowledge of LD is to focus on the substrates that are ubiquitinated by the E3-ubiquitin ligase Malin. Some substrates have already been provided by previous studies based on protein-protein interaction techniques and have been associated with some alterations that mark the disease. In this work, we have used an unbiased alternative approach based on the activity of Malin as an E3-ubiquitin ligase. We report the discovery of novel bonafide substrates of Malin and have characterized one of them more deeply, namely PIP3-dependent Rac exchanger 1 (P-Rex1). The analysis conducted upon this substrate sets the genesis of the delineation of a molecular pathway that leads to altered glucose uptake, which could be one of the origin of the accumulation of the polyglucosans present in the disease. | es_ES |
dc.description.sponsorship | We want to thank Dr. Atanasio Pandiella (CIC-Salamanca), Dr. Manuel Rodríguez (Proteomics Unit. CIC-bioGUNE. Bizkaia. Spain), and Dr. Ch. Blattner (Institute of Toxicology and Genetics. Karlsruhe Institute of Technology. Karlsruhe. Germany) for plasmids. We also thank the support provided by SGIker Proteomics service (UPV/EHU - ERDF. EU). This work has received funding from the European Union's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement 813599 (TRIM-NET). We also want to acknowledge the support of the grant from the National Institutes of Health P01 NS097197, which established the Lafora Epilepsy Cure Initiative (LECI), and a grant from la Fundació La Marató TV3 (202032), to PS; and a grant from the Spanish Ministry of Science and Innovation PID2020-112972RB-I00 to PS and MGG. | es_ES |
dc.language.iso | eng | es_ES |
dc.publisher | Elsevier | es_ES |
dc.relation | info:eu-repo/grantAgreement/EC/H2020/813599 | es_ES |
dc.relation | info:eu-repo/grantAgreement/MICINN/PID2020-112972RB-I00 | es_ES |
dc.rights | info:eu-repo/semantics/openAccess | es_ES |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/3.0/es/ | * |
dc.subject | Lafora disease | es_ES |
dc.subject | ubiquitination | es_ES |
dc.subject | quantitative proteomics | es_ES |
dc.subject | bioUb | es_ES |
dc.subject | P-Rex1 | es_ES |
dc.subject | Rac1 | es_ES |
dc.subject | Malin | es_ES |
dc.title | P-Rex1 is a novel substrate of the E3 ubiquitin ligase Malin associated with Lafora disease | es_ES |
dc.type | info:eu-repo/semantics/article | es_ES |
dc.rights.holder | © 2023 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-
nc-nd/4.0/). | es_ES |
dc.rights.holder | Atribución-NoComercial-SinDerivadas 3.0 España | * |
dc.relation.publisherversion | https://www.sciencedirect.com/science/article/pii/S0969996123000128?via%3Dihub | es_ES |
dc.identifier.doi | 10.1016/j.nbd.2023.105998 | |
dc.contributor.funder | European Commission | |
dc.departamentoes | Bioquímica y biología molecular | es_ES |
dc.departamentoeu | Biokimika eta biologia molekularra | es_ES |