Browsing by Subject "Lafora Disease"

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    Are there errors in glycogen biosynthesis and is laforin a repair enzyme?
    (Elsevier, 2011-10-20) Roach, Peter J.; Department of Biochemistry & Molecular Biology, IU School of Medicine
    Glycogen, a branched polymer of glucose, is well known as a cellular reserve of metabolic energy and/or biosynthetic precursors. Besides glucose, however, glycogen contains small amounts of covalent phosphate, present as C2 and C3 phosphomonoesters. Current evidence suggests that the phosphate is introduced by the biosynthetic enzyme glycogen synthase as a rare alternative to its normal catalytic addition of glucose units. The phosphate can be removed by the laforin phosphatase, whose mutation causes a fatal myoclonus epilepsy called Lafora disease. The hypothesis is that glycogen phosphorylation can be considered a catalytic error and laforin a repair enzyme.
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    Glycogen metabolism in Lafora disease
    (2018-02) Contreras, Christopher J.; Roach, Peter J.; DePaoli-Roach, Anna A.; Hurley, Thomas D.; Herring, B. Paul
    Glycogen, a branched polymer of glucose, serves as an osmotically neutral means of storing glucose. Covalent phosphate is a trace component of mammalian glycogen and has been a point of interest with respect to Lafora disease, a fatal form of juvenile myoclonus epilepsy. Mutations in either the EPM2A or EPM2B genes, which encode laforin and malin respectively, account for ~90% of disease cases. A characteristic of Lafora disease is the formation of Lafora bodies, which are mainly composed of an excess amount of abnormal glycogen that is poorly branched and insoluble. Laforin-/- and malin-/- knockout mice share several characteristics of the human disease, formation of Lafora bodies in various tissues, increased glycogen phosphorylation and development of neurological symptoms. The source of phosphate in glycogen has been an area of interest and here we provide evidence that glycogen synthase is capable of incorporating phosphate into glycogen. Mice lacking the glycogen targeting subunit PTG of the PP1 protein phosphatase have decreased glycogen stores in a number of tissues. When crossed with mice lacking either laforin or malin, the double knockout mice no longer over-accumulate glycogen, Lafora body formation is almost absent and the neurological disorders are normalized. Another question has been whether the abnormal glycogen in the Lafora disease mouse models can be metabolized. Using exercise to provoke glycogen degradation, we show that in laforin-/- and malin-/- mice the insoluble, abnormal glycogen appears to be metabolically inactive. These studies suggest that a therapeutic approach to Lafora disease may be to reduce the overall glycogen levels in cells so that insoluble, metabolically inert pools of the polysaccharide do not accumulate.
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    Protein degradation and quality control in cells from laforin and malin knockout mice
    (ASBMB, 2014-07-25) Garyali, Punitee; Segvich, Dyann M.; DePaoli-Roach, Anna A.; Roach, Peter J.; Department of Biochemistry & Molecular Biology, IU School of Medicine
    Lafora disease is a progressive myoclonus epilepsy caused by mutations in the EPM2A or EPM2B genes that encode a glycogen phosphatase, laforin, and an E3 ubiquitin ligase, malin, respectively. Lafora disease is characterized by accumulation of insoluble, poorly branched, hyperphosphorylated glycogen in brain, muscle, heart, and liver. The laforinmalin complex has been proposed to play a role in the regulation of glycogen metabolism and protein quality control. We evaluated three arms of the protein degradation/ quality control process (the autophago-lysosomal pathway, the ubiquitin-proteasomal pathway, and the endoplasmic reticulum (ER) stress response) in mouse embryonic fibroblasts from Epm2a(-/-), Epm2b(-/-), and Epm2a(-/-) Epm2b(-/-) mice. The levels of LC3-II, a marker of autophagy, were decreased in all knock-out cells as compared with wild type even though they still showed a slight response to starvation and rapamycin. Furthermore, ribosomal protein S6 kinase and S6 phosphorylation were increased. Under basal conditions there was no effect on the levels of ubiquitinated proteins in the knock-out cells, but ubiquitinated protein degradation was decreased during starvation or stress. Lack of malin (Epm2b(-/-) and Epm2a(-/-) Epm2b(-/-) cells) but not laforin (Epm2a(-/-) cells) decreased LAMP1, a lysosomal marker. CHOP expression was similar in wild type and knock-out cells under basal conditions or with ER stress-inducing agents. In conclusion, both laforin and malin knock-out cells display mTOR-dependent autophagy defects and reduced proteasomal activity but no defects in the ER stress response. We speculate that these defects may be secondary to glycogen overaccumulation. This study also suggests a malin function independent of laforin, possibly in lysosomal biogenesis and/or lysosomal glycogen disposal.
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    Targeting Pathogenic Lafora Bodies in Lafora Disease Using an Antibody-Enzyme Fusion
    (Elsevier, 2019-07-25) Brewer, M. Kathryn; Uittenbogaard, Annette; Austin, Grant L.; Segvich, Dyann M.; DePaoli-Roach, Anna; Roach, Peter J.; McCarthy, John J.; Simmons, Zoe R.; Brandon, Jason A.; Zhou, Zhengqiu; Zeller, Jill; Young, Lyndsay E. A.; Sun, Ramon C.; Pauly, James R.; Aziz, Nadine M.; Hodges, Bradley L.; McKnight, Tracy R.; Armstrong, Dustin D.; Gentry, Matthew S.; Biochemistry and Molecular Biology, School of Medicine