From The Cover: 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: 9.67). 07/2005; 102(24):8501-6. DOI: 10.1073/pnas.0503285102
Source: PubMed


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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    • "The symptoms of LD include the disease defining myoclonic epilepsy, ataxia, dementia and cognitive defects [1] [2]. Being an autosomal recessive disorder, LD is caused by mutations in both copies of either the EPM2A gene coding for the protein phosphatase laforin [3] [4] or the NHLRC1 gene coding for an E3 ubiquitin ligase named malin [5] [6]. Studies have revealed that laforin and malin are recruited to aggresomes upon proteasomal impairment, and as a functional complex, promote the degradation of cytotoxic misfolded proteins [7] [8]. "
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    ABSTRACT: Lafora disease (LD) is an autosomal recessive, progressive, and fatal form of a neurodegenerative disorder characterized by the presence of Lafora polyglucosan bodies. LD is caused by defects in either the laforin protein phosphatase or the malin E3 ubiquitin ligase. Laforin and malin were shown play key roles in proteolytic processes, unfolded stress response, and glycogen metabolism. Therefore, the LD proteins laforin and malin are thought to function as pro-survival factors and their loss thus could result in neurodegeneration. To understand the molecular pathway leading to the cell death in LD, in the present study, we investigated the possible role of LD proteins in the p53-mediated cell death pathway. We show that loss of laforin or malin results in the increased level and activity of p53, both in cellular and animal models of LD, and that this is primarily due to the increased levels of Hipk2, a proapoptotic activator of p53. Overexpression of laforin or malin confers protection against Hipk2-mediated cell death by targeting the Hipk2 to the cytoplasmic compartment. Taken together, our study strengthens the notion that laforin and malin are pro-survival factors, and that the activation of Hipk2-p53 cell death pathway might underlie neurodegeneration in LD. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · Jun 2015 · Biochemical and Biophysical Research Communications
    • "In the absence of laforin, glycogen becomes highly phosphorylated and less branched, decreasing the solubility of this polysaccharide [21] [22] [23] and leading to the formation of LBs (Fig. 1). Second, it is known that laforin interacts physically with malin, forming a functional complex [16] [17] [37]. In this complex, laforin would recruit specific substrates to be ubiquitinated by malin (see Proteolytic impairment in Lafora disease). "
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    ABSTRACT: Lafora Disease (LD, OMIM 254780, ORPHA501) is a devastating neurodegenerative disorder characterized by the presence of glycogen-like intracellular inclusions called Lafora bodies and caused, in most cases, by mutations in either EPM2A or EPM2B genes, encoding respectively laforin, a phosphatase with dual specificity that is involved in the dephosphorylation of glycogen, and malin, an E3-ubiquitin ligase involved in the polyubiquitination of proteins related with glycogen metabolism. Thus, it has been reported that laforin and malin form a functional complex that acts as a key regulator of glycogen metabolism and that also plays a crucial role in protein homeostasis (proteostasis). In relationship with this last function, it has been shown that cells are more sensitive to ER-stress and show defects in proteasome and autophagy activities in the absence of a functional laforin-malin complex. More recently, we have demonstrated that oxidative stress accompanies these proteostasis defects and that various LD models show an increase in reactive oxygen species and oxidative stress products together with a dysregulated antioxidant enzyme expression and activity. In this review we discuss possible connections between the multiple defects in protein homeostasis present in LD with oxidative stress. Copyright © 2015. Published by Elsevier Inc.
    No preview · Article · Feb 2015 · Free Radical Biology and Medicine
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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.
    Full-text · Article · Sep 2014 · Frontiers in Neuroscience
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