Article

Insights into Lafora disease: Malin is an E3 ubiquitin ligase that ubiquitinates and promotes the degradation of laforin

Department of Pharmacology, School of Medicine, University of California at San Diego, La Jolla, CA 92093-0721, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 07/2005; 102(24):8501-6. DOI: 10.1073/pnas.0503285102
Source: PubMed

ABSTRACT Lafora disease (LD) is a fatal form of progressive myoclonus epilepsy caused by recessive mutations in either a gene encoding a dual-specificity phosphatase, known as laforin, or a recently identified gene encoding the protein known as malin. Here, we demonstrate that malin is a single subunit E3 ubiquitin (Ub) ligase and that its RING domain is necessary and sufficient to mediate ubiquitination. Additionally, malin interacts with and polyubiquitinates laforin, leading to its degradation. Missense mutations in malin that are present in LD patients abolish its ability to polyubiquitinate and signal the degradation of laforin. Our results demonstrate that laforin is a physiologic substrate of malin, and we propose possible models to explain how recessive mutations in either malin or laforin result in LD. Furthermore, these data distinguish malin as an E3 Ub ligase whose activity is necessary to prevent a neurodegenerative disease that involves formation of nonproteinacious inclusion bodies.

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Available from: Jack E Dixon, Jul 28, 2015
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    • "Lafora disease (LD) is a rare form of inherited progressive myoclonus epilepsy (OMIM#254780; ORPHA501). Recessive mutations in either the EPM2A gene encoding a dual-specificity phosphatase known as laforin (OMIM 607566) (Minassian et al., 1998; Serratosa et al., 1999) or in the EPM2B/NHLRC1 gene encoding malin (OMIM 608072), an E3 ubiquitin ligase (Chan et al., 2003; Gentry et al., 2005; Gomez-Abad et al., 2005; Singh et al., 2005, 2006) are responsible for the disease, although the existence of a third, minor locus has also been postulated (Chan et al., 2004). Patients with LD develop progressive myoclonus epilepsy that usually starts in adolescence and includes absence, visual, myoclonic, and tonic-clonic seizures accompanied by rapid neurologic degeneration, including ataxia, dementia, dysarthria, amaurosis, respiratory failure, and a final vegetative state and death, usually within 10 years of onset (Lafora, 1911; Van Heycop Ten Ham, 1974; Berkovic et al., 1986, 1991; Roger et al., 1992; Acharya et al., 1995). "
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    ABSTRACT: Lafora disease is a rare form of inherited progressive myoclonus epilepsy caused by mutations in the EPM2A gene encoding laforin, or in the EPM2B gene, which encodes malin. It is characterized by the presence of polyglucosan inclusion bodies (Lafora bodies) in brain and other tissues. Genetically engineered mice lacking expression of either the laforin (Epm2a(-/-) ) or malin (Epm2b(-/-) ) genes display a number of neurological and behavioral abnormalities that resemble those found in patients suffering from Lafora disease; of these, both Epm2a(-/-) and Epm2b(-/-) mice have shown altered motor activity, impaired motor coordination, episodic memory deficits, and different degrees of spontaneous epileptic activity. In this study, we analyze the sensitivity of Epm2a(-/-) and Epm2b(-/-) mice to the convulsant drug pentylenetetrazol (PTZ), an antagonist of the γ-aminobutyric acid type A (GABAA) receptor, commonly used to induce epileptic tonic-clonic seizures in laboratory animals. PTZ-induced epileptic activity, including myoclonic jerks and tonic-clonic seizures, was analyzed in 2 age groups of mice comprising representative samples of young adult and aged mice, after administration of PTZ at sub-convulsive and convulsive doses. Epm2a(-/-) and Epm2b(-/-) mice showed a lower convulsive threshold after PTZ injections at sub-convulsive doses. A lower convulsive threshold and shorter latencies to develop epileptic seizures were observed after PTZ injections at convulsive doses. Different patterns of generalized seizures and of discharges were observed in Epm2a(-/-) and Epm2b(-/-) mice. Epm2a(-/-) and Epm2b(-/-) mice present an increased sensitivity to the convulsant agent PTZ that may reflect different degrees of increased GABAA receptor-mediated hyperexcitability.
    Frontiers in Neuroscience 09/2014; 8:291. DOI:10.3389/fnins.2014.00291 · 3.70 Impact Factor
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    • "Laforin and malin interact with each other and colocalize in endoplasmic reticulum [3] [4]. Besides being a substrate to malin, laforin also work together with malin as a complex to promote the degradation of malin targets through the ubiquitin proteasome system [3] [4] [5]. "
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    ABSTRACT: The EPM2A gene, defective in the fatal neurodegenerative disorder Lafora disease (LD), is known to encode two distinct proteins by differential splicing; a phosphatase active cytoplasmic isoform and a phosphatase inactive nuclear isoform. We report here the identification of three novel EPM2A splice variants with potential to code for five distinct proteins in alternate reading frames. These novel isoforms, when ectopically expressed in cell lines, show distinct subcellular localization, interact with and serve as substrates of malin ubiquitin ligase-the second protein defective in LD. Two phosphatase active isoforms interact to form a heterodimeric complex that is inactive as a phosphatase in vitro, suggesting an antagonistic function for laforin isoforms if expressed endogenously in significant amounts in human tissues. Thus alternative splicing could possibly be one of the mechanisms by which EPM2A may regulate the cellular functions of the proteins it codes for.
    Genomics 01/2012; 99(1):36-43. DOI:10.1016/j.ygeno.2011.10.001 · 2.79 Impact Factor
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    • "Glycogen isolated from a pool of KO brains was clearly less branched (peak at 537 nm) than that from control brains (peak at 492 nm) (Fig 2B). Malin KO mice accumulate MGS in LBs Malin has been reported to be involved in the proteasomal clearance of laforin (Gentry et al, 2005) and MGS (Vilchez et al, 2007). Therefore, we analysed the MGS content and distribution in brain sections from WT and malin KO mice. "
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    ABSTRACT: Lafora disease (LD) is caused by mutations in either the laforin or malin gene. The hallmark of the disease is the accumulation of polyglucosan inclusions called Lafora Bodies (LBs). Malin knockout (KO) mice present polyglucosan accumulations in several brain areas, as do patients of LD. These structures are abundant in the cerebellum and hippocampus. Here, we report a large increase in glycogen synthase (GS) in these mice, in which the enzyme accumulates in LBs. Our study focused on the hippocampus where, under physiological conditions, astrocytes and parvalbumin-positive (PV(+)) interneurons expressed GS and malin. Although LBs have been described only in neurons, we found this polyglucosan accumulation in the astrocytes of the KO mice. They also had LBs in the soma and some processes of PV(+) interneurons. This phenomenon was accompanied by the progressive loss of these neuronal cells and, importantly, neurophysiological alterations potentially related to impairment of hippocampal function. Our results emphasize the relevance of the laforin-malin complex in the control of glycogen metabolism and highlight altered glycogen accumulation as a key contributor to neurodegeneration in LD.
    EMBO Molecular Medicine 11/2011; 3(11):667-81. DOI:10.1002/emmm.201100174 · 8.25 Impact Factor
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