A role for AGL ubiquitination in the glycogen storage disorders of Lafora and Cori’s disease

Cheng, Alan; Zhang, Mei; Gentry, Matthew S.; Worby, Carolyn A.; Dixon, Jack E.; Saltiel, Alan R.

doi:10.1101/gad.1553207

Cited by 92 publications

(95 citation statements)

References 35 publications

(38 reference statements)

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“…The beads were resuspended in 30 l of 4ϫ NuPage sample buffer (Invitrogen) and subjected to Western analyses. Denaturing IPs were performed as described (29). Western blots were probed with the following antibodies: ␣-FLAG (Sigma), ␣-myc 9E10 (Sigma), ␣-V5 (Invitrogen), ␣-ubiquitin (Covance), avidin-HRP (Boston Biochem), ␣-laforin, ␣-malin, or ␣-PTG.…”

Section: Methodsmentioning

confidence: 99%

“…In addition to PTG, malin ubiquitinates laforin and targets it for degradation (26). Malin was also recently shown to ubiquitinate glycogen debranching enzyme (AGL/GDE) and target it for proteasome-dependent degradation (29). The ubiquitination of AGL also occurred in the absence of a detectable interaction between malin and AGL.…”

Section: S-ptg (Data Not Shown)mentioning

confidence: 99%

“…Malin was recently shown to ubiquitinate glycogen debranching enzyme (AGL/GDE) and target it for degradation as well (29).…”

mentioning

confidence: 99%

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Malin Decreases Glycogen Accumulation by Promoting the Degradation of Protein Targeting to Glycogen (PTG)

Worby

Gentry

Dixon

2008

Journal of Biological Chemistry

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146

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Lafora disease (LD) is an autosomal recessive neurodegenerative disease that results in progressive myoclonus epilepsy and death. LD is caused by mutations in either the E3 ubiquitin ligase malin or the dual specificity phosphatase laforin. A hallmark of LD is the accumulation of insoluble glycogen in the cytoplasm of cells from most tissues. Glycogen metabolism is regulated by phosphorylation of key metabolic enzymes. One regulator of this phosphorylation is protein targeting to glycogen (PTG/R5), a scaffold protein that binds both glycogen and many of the enzymes involved in glycogen synthesis, including protein phosphatase 1 (PP1), glycogen synthase, phosphorylase, and laforin. Overexpression of PTG markedly increases glycogen accumulation, and decreased PTG expression decreases glycogen stores. To investigate if malin and laforin play a role in glycogen metabolism, we overexpressed PTG, malin, and laforin in tissue culture cells. We found that expression of malin or laforin decreased PTG-stimulated glycogen accumulation by 25%, and co-expression of malin and laforin abolished PTG-stimulated glycogen accumulation. Consistent with this result, we found that malin ubiquitinates PTG in a laforin-dependent manner, both in vivo and in vitro, and targets PTG for proteasome-dependent degradation. These results suggest an additional mechanism, involving laforin and malin, in regulating glycogen metabolism.

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Section: Methodsmentioning

confidence: 99%

Section: S-ptg (Data Not Shown)mentioning

confidence: 99%

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Malin Decreases Glycogen Accumulation by Promoting the Degradation of Protein Targeting to Glycogen (PTG)

Worby

Gentry

Dixon

2008

Journal of Biological Chemistry

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146

157

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“…Laforin-laforin and laforin-malin interactions (identified by double headed arrows) have also been reported [Dubey and Ganesh., 2008;Ferná ndez-Sá nchez et al, 2003;Gentry et al, 2005;Liu et al, 2006]. Malin interacts with ubiquitin conjugating enzymes (UbcH2, UbcH5a, UbcH5c, and UbcH6) [Gentry et al, 2005] and the glycogen debranching enzyme, AGL [Cheng et al, 2007]. (CBD, carbohydrate-binding domain; DSPD, dual-specificity phosphatase domain; RING, RING finger domain; NHL, NHL repeats).…”

Section: Mutational Spectrum Of Epm2a and Nhlrc1 Genesmentioning

confidence: 99%

“…An abnormal raise in the cellular levels of PTG, because of the absence of laforin or malin, leads to glycogen accumulation and apoptotic cell death in a cellular model for LD [Vilchez et al, 2007]. Malin was also shown to degrade the glycogen debranching enzyme (AGL) [Cheng et al, 2007] (see Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

Lafora progressive myoclonus epilepsy: A meta-analysis of reported mutations in the first decade following the discovery of theEPM2AandNHLRC1genes

2009

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Lafora disease (LD) is an autosomal recessive and fatal form of progressive myoclonus epilepsy. LD patients manifest myoclonus and tonic-clonic seizures, visual hallucinations, and progressive neurologic deterioration beginning at 12 to 15 years of age. The two genes known to be associated with LD are EPM2A and NHLRC1. Mutations in at least one other as yet unknown gene also cause LD. The EMP2A encodes a protein phosphatase and NHLRC1 encodes an ubiquitin ligase. These two proteins interact with each other and, as a complex, are thought to regulate critical neuronal functions. Nearly 100 distinct mutations have been discovered in the two genes in over 200 independent LD families. Nearly half of them are missense mutations, and the deletion mutations account for one-quarter. Several reports have provided functional data for the mutant proteins and a few also provide genotype-phenotype correlations. In this review we provide an update on the spectrum of EPM2A and NHLRC1 mutations, and discuss their distribution in the patient population, genotype-phenotype correlations, and on the possible effect of disease mutations on the cellular functions of LD proteins.

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Broad Spectrum of Hepatocyte Inclusions in Humans, Animals, and Experimental Models

Strnad

Nuraldeen

Güldiken

et al. 2013

Comprehensive Physiology

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We focus on hepatic inclusions, which are defined as intracellular aggregates of stainable substances. They represent established hallmarks of their respective human disorders, but unlike aggregates found in neurodegenerative disorders are often not well studied. Hepatic inclusions can be subdivided into primary liver aggregates and aggregates found in multiple tissues. The former ones consist of inclusions found in endoplasmic reticulum storage diseases such as α 1-antitrypsin aggregates or ground-glass hepatocytes, p62-containing (Mallory-Denk bodies and intracellular hyaline bodies) and porphyrin-containing inclusions. p62-containing aggregates are not restricted to the liver but are found in multiple other disorders such as Parkinson or Alzheimer disease. Inclusions such as pale bodies or intracellular hyaline bodies are typical for malignant disorders while others (ground-glass hepatocytes and α1-antitrypsin aggregates) are predominantly seen in non-neoplastic tissues. The inclusions, which are not restricted to the liver, are often due to a systemic viral infection, but also due to disruption of glycogen metabolism or systemic inclusion-forming diseases such as polyglutamine disorders or sarcoidosis. Despite their heterogeneity, inclusions share several pathogenic principles such as an imbalance between protein damage/misfolding on one side and repair/degradation on the other side. This is why hepatic aggregates represent a valuable tool to study the aggregation process in general and to improve our understanding of inclusions found in multiple human disorders.

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A role for AGL ubiquitination in the glycogen storage disorders of Lafora and Cori’s disease

Cited by 92 publications

References 35 publications

Malin Decreases Glycogen Accumulation by Promoting the Degradation of Protein Targeting to Glycogen (PTG)

Malin Decreases Glycogen Accumulation by Promoting the Degradation of Protein Targeting to Glycogen (PTG)

Lafora progressive myoclonus epilepsy: A meta-analysis of reported mutations in the first decade following the discovery of theEPM2AandNHLRC1genes

Broad Spectrum of Hepatocyte Inclusions in Humans, Animals, and Experimental Models

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