Genetic depletion of the malin e3 ubiquitin ligase in mice leads to Lafora bodies and the accumulation of insoluble laforin

Anna A. DePaoli-Roach, Vincent S. Tagliabracci, Dyann M. Segvich, Catalina M. Meyer, Jose M. Irimia, Peter J. Roach

Research output: Contribution to journalArticle

76 Citations (Scopus)

Abstract

Approximately 90% of cases of Lafora disease, a fatal teenage-onset progressive myoclonus epilepsy, are caused by mutations in either the EPM2A or the EPM2B genes that encode, respectively, a glycogen phosphatase called laforin and an E3 ubiquitin ligase called malin. Lafora disease is characterized by the formation of Lafora bodies, insoluble deposits containing poorly branched glycogen or polyglucosan, in many tissues including skeletal muscle, liver, and brain. Disruption of the Epm2b gene in mice resulted in viable animals that, by 3 months of age, accumulated Lafora bodies in the brain and to a lesser extent in heart and skeletal muscle. Analysis of muscle and brain of the Epm2b -/- mice by Western blotting indicated no effect on the levels of glycogen synthase, PTG (type 1 phosphatase-targeting subunit), or debranching enzyme, making it unlikely that these proteins are targeted for destruction by malin, as has been proposed. Total laforin protein was increased in the brain of Epm2b-/- mice and, most notably, was redistributed from the soluble, low speed supernatant to the insoluble low speed pellet, which now contained 90% of the total laforin. This result correlated with elevated insolubility of glycogen and glycogen synthase. Because up-regulation of laforin cannot explain Lafora body formation, we conclude that malin functions to maintain laforin associated with soluble glycogen and that its absence causes sequestration of laforin to an insoluble polysaccharide fraction where it is functionally inert.

Original languageEnglish (US)
Pages (from-to)25372-25381
Number of pages10
JournalJournal of Biological Chemistry
Volume285
Issue number33
DOIs
StatePublished - Aug 13 2010

Fingerprint

Ubiquitin-Protein Ligases
Glycogen
Brain
Lafora Disease
Muscle
Glycogen Synthase
Phosphoric Monoester Hydrolases
Skeletal Muscle
Genes
Progressive Myoclonic Epilepsy
Liver
Polysaccharides
Myocardium
Animals
Proteins
Up-Regulation
Deposits
Solubility
Western Blotting
Tissue

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Genetic depletion of the malin e3 ubiquitin ligase in mice leads to Lafora bodies and the accumulation of insoluble laforin. / DePaoli-Roach, Anna A.; Tagliabracci, Vincent S.; Segvich, Dyann M.; Meyer, Catalina M.; Irimia, Jose M.; Roach, Peter J.

In: Journal of Biological Chemistry, Vol. 285, No. 33, 13.08.2010, p. 25372-25381.

Research output: Contribution to journalArticle

DePaoli-Roach, Anna A. ; Tagliabracci, Vincent S. ; Segvich, Dyann M. ; Meyer, Catalina M. ; Irimia, Jose M. ; Roach, Peter J. / Genetic depletion of the malin e3 ubiquitin ligase in mice leads to Lafora bodies and the accumulation of insoluble laforin. In: Journal of Biological Chemistry. 2010 ; Vol. 285, No. 33. pp. 25372-25381.
@article{ec8d358c9198428d81df0d97a93b913a,
title = "Genetic depletion of the malin e3 ubiquitin ligase in mice leads to Lafora bodies and the accumulation of insoluble laforin",
abstract = "Approximately 90{\%} of cases of Lafora disease, a fatal teenage-onset progressive myoclonus epilepsy, are caused by mutations in either the EPM2A or the EPM2B genes that encode, respectively, a glycogen phosphatase called laforin and an E3 ubiquitin ligase called malin. Lafora disease is characterized by the formation of Lafora bodies, insoluble deposits containing poorly branched glycogen or polyglucosan, in many tissues including skeletal muscle, liver, and brain. Disruption of the Epm2b gene in mice resulted in viable animals that, by 3 months of age, accumulated Lafora bodies in the brain and to a lesser extent in heart and skeletal muscle. Analysis of muscle and brain of the Epm2b -/- mice by Western blotting indicated no effect on the levels of glycogen synthase, PTG (type 1 phosphatase-targeting subunit), or debranching enzyme, making it unlikely that these proteins are targeted for destruction by malin, as has been proposed. Total laforin protein was increased in the brain of Epm2b-/- mice and, most notably, was redistributed from the soluble, low speed supernatant to the insoluble low speed pellet, which now contained 90{\%} of the total laforin. This result correlated with elevated insolubility of glycogen and glycogen synthase. Because up-regulation of laforin cannot explain Lafora body formation, we conclude that malin functions to maintain laforin associated with soluble glycogen and that its absence causes sequestration of laforin to an insoluble polysaccharide fraction where it is functionally inert.",
author = "DePaoli-Roach, {Anna A.} and Tagliabracci, {Vincent S.} and Segvich, {Dyann M.} and Meyer, {Catalina M.} and Irimia, {Jose M.} and Roach, {Peter J.}",
year = "2010",
month = "8",
day = "13",
doi = "10.1074/jbc.M110.148668",
language = "English (US)",
volume = "285",
pages = "25372--25381",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "33",

}

TY - JOUR

T1 - Genetic depletion of the malin e3 ubiquitin ligase in mice leads to Lafora bodies and the accumulation of insoluble laforin

AU - DePaoli-Roach, Anna A.

AU - Tagliabracci, Vincent S.

AU - Segvich, Dyann M.

AU - Meyer, Catalina M.

AU - Irimia, Jose M.

AU - Roach, Peter J.

PY - 2010/8/13

Y1 - 2010/8/13

N2 - Approximately 90% of cases of Lafora disease, a fatal teenage-onset progressive myoclonus epilepsy, are caused by mutations in either the EPM2A or the EPM2B genes that encode, respectively, a glycogen phosphatase called laforin and an E3 ubiquitin ligase called malin. Lafora disease is characterized by the formation of Lafora bodies, insoluble deposits containing poorly branched glycogen or polyglucosan, in many tissues including skeletal muscle, liver, and brain. Disruption of the Epm2b gene in mice resulted in viable animals that, by 3 months of age, accumulated Lafora bodies in the brain and to a lesser extent in heart and skeletal muscle. Analysis of muscle and brain of the Epm2b -/- mice by Western blotting indicated no effect on the levels of glycogen synthase, PTG (type 1 phosphatase-targeting subunit), or debranching enzyme, making it unlikely that these proteins are targeted for destruction by malin, as has been proposed. Total laforin protein was increased in the brain of Epm2b-/- mice and, most notably, was redistributed from the soluble, low speed supernatant to the insoluble low speed pellet, which now contained 90% of the total laforin. This result correlated with elevated insolubility of glycogen and glycogen synthase. Because up-regulation of laforin cannot explain Lafora body formation, we conclude that malin functions to maintain laforin associated with soluble glycogen and that its absence causes sequestration of laforin to an insoluble polysaccharide fraction where it is functionally inert.

AB - Approximately 90% of cases of Lafora disease, a fatal teenage-onset progressive myoclonus epilepsy, are caused by mutations in either the EPM2A or the EPM2B genes that encode, respectively, a glycogen phosphatase called laforin and an E3 ubiquitin ligase called malin. Lafora disease is characterized by the formation of Lafora bodies, insoluble deposits containing poorly branched glycogen or polyglucosan, in many tissues including skeletal muscle, liver, and brain. Disruption of the Epm2b gene in mice resulted in viable animals that, by 3 months of age, accumulated Lafora bodies in the brain and to a lesser extent in heart and skeletal muscle. Analysis of muscle and brain of the Epm2b -/- mice by Western blotting indicated no effect on the levels of glycogen synthase, PTG (type 1 phosphatase-targeting subunit), or debranching enzyme, making it unlikely that these proteins are targeted for destruction by malin, as has been proposed. Total laforin protein was increased in the brain of Epm2b-/- mice and, most notably, was redistributed from the soluble, low speed supernatant to the insoluble low speed pellet, which now contained 90% of the total laforin. This result correlated with elevated insolubility of glycogen and glycogen synthase. Because up-regulation of laforin cannot explain Lafora body formation, we conclude that malin functions to maintain laforin associated with soluble glycogen and that its absence causes sequestration of laforin to an insoluble polysaccharide fraction where it is functionally inert.

UR - http://www.scopus.com/inward/record.url?scp=77955486949&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77955486949&partnerID=8YFLogxK

U2 - 10.1074/jbc.M110.148668

DO - 10.1074/jbc.M110.148668

M3 - Article

C2 - 20538597

AN - SCOPUS:77955486949

VL - 285

SP - 25372

EP - 25381

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 33

ER -