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Lafora Disease: A Ubiquitination-Related Pathology

Lafora disease (LD, OMIM254780) is a rare and fatal form of progressive myoclonus epilepsy (PME). Among PMEs, LD is unique because of the rapid neurological deterioration of the patients and the appearance in brain and peripheral tissues of insoluble glycogen-like (polyglucosan) inclusions, named La...

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Autores principales: García-Gimeno, Maria Adelaida, Knecht, Erwin, Sanz, Pascual
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6116066/
https://www.ncbi.nlm.nih.gov/pubmed/30050012
http://dx.doi.org/10.3390/cells7080087
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author García-Gimeno, Maria Adelaida
Knecht, Erwin
Sanz, Pascual
author_facet García-Gimeno, Maria Adelaida
Knecht, Erwin
Sanz, Pascual
author_sort García-Gimeno, Maria Adelaida
collection PubMed
description Lafora disease (LD, OMIM254780) is a rare and fatal form of progressive myoclonus epilepsy (PME). Among PMEs, LD is unique because of the rapid neurological deterioration of the patients and the appearance in brain and peripheral tissues of insoluble glycogen-like (polyglucosan) inclusions, named Lafora bodies (LBs). LD is caused by mutations in the EPM2A gene, encoding the dual phosphatase laforin, or the EPM2B gene, encoding the E3-ubiquitin ligase malin. Laforin and malin form a functional complex that is involved in the regulation of glycogen synthesis. Thus, in the absence of a functional complex glycogen accumulates in LBs. In addition, it has been suggested that the laforin-malin complex participates in alternative physiological pathways, such as intracellular protein degradation, oxidative stress, and the endoplasmic reticulum unfolded protein response. In this work we review the possible cellular functions of laforin and malin with a special focus on their role in the ubiquitination of specific substrates. We also discuss here the pathological consequences of defects in laforin or malin functions, as well as the therapeutic strategies that are being explored for LD.
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spelling pubmed-61160662018-08-31 Lafora Disease: A Ubiquitination-Related Pathology García-Gimeno, Maria Adelaida Knecht, Erwin Sanz, Pascual Cells Review Lafora disease (LD, OMIM254780) is a rare and fatal form of progressive myoclonus epilepsy (PME). Among PMEs, LD is unique because of the rapid neurological deterioration of the patients and the appearance in brain and peripheral tissues of insoluble glycogen-like (polyglucosan) inclusions, named Lafora bodies (LBs). LD is caused by mutations in the EPM2A gene, encoding the dual phosphatase laforin, or the EPM2B gene, encoding the E3-ubiquitin ligase malin. Laforin and malin form a functional complex that is involved in the regulation of glycogen synthesis. Thus, in the absence of a functional complex glycogen accumulates in LBs. In addition, it has been suggested that the laforin-malin complex participates in alternative physiological pathways, such as intracellular protein degradation, oxidative stress, and the endoplasmic reticulum unfolded protein response. In this work we review the possible cellular functions of laforin and malin with a special focus on their role in the ubiquitination of specific substrates. We also discuss here the pathological consequences of defects in laforin or malin functions, as well as the therapeutic strategies that are being explored for LD. MDPI 2018-07-26 /pmc/articles/PMC6116066/ /pubmed/30050012 http://dx.doi.org/10.3390/cells7080087 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
García-Gimeno, Maria Adelaida
Knecht, Erwin
Sanz, Pascual
Lafora Disease: A Ubiquitination-Related Pathology
title Lafora Disease: A Ubiquitination-Related Pathology
title_full Lafora Disease: A Ubiquitination-Related Pathology
title_fullStr Lafora Disease: A Ubiquitination-Related Pathology
title_full_unstemmed Lafora Disease: A Ubiquitination-Related Pathology
title_short Lafora Disease: A Ubiquitination-Related Pathology
title_sort lafora disease: a ubiquitination-related pathology
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6116066/
https://www.ncbi.nlm.nih.gov/pubmed/30050012
http://dx.doi.org/10.3390/cells7080087
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