An inducible glycogen synthase-1 knockout halts but does not reverse Lafora disease progression in mice

Nitschke, Silvia; Chown, Erin E.; Zhao, Xiaochu; Gabrielian, Shoghig; Petković, Sara; Guisso, Dikran R; Perri, Ami M.; Wang, Peixiang; Ahonen, Saija; Nitschké, Felix; Minassian, Berge A.

doi:10.1074/jbc.ra120.015773

Cited by 25 publications

(18 citation statements)

References 48 publications

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“…By activating glycogen synthase phosphatase, insulin activates GYS, increases the ability of liver and muscle to synthesize glycogen, inhibits the production of endogenous glucose and stimulates the uptake of glucose in peripheral tissues. [44][45][46] Protein phosphatase 1 (PP1) is the main phosphatase in the insulin-activated glycogen synthase pathway, consisting of 37KDa catalytic subunit (PPlC) and 126KDa regulatory subunit (PPlG). 47 For personal use only.…”

Section: Discussionmentioning

confidence: 99%

miR-140-5p Aggravates Insulin Resistance via Directly Targeting GYS1 and PPP1CC in Insulin-Resistant HepG2 Cells

Yan

Wang

et al. 2021

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Background Much attention has been paid to the regulatory role of microRNA (miRNA) in insulin resistance. Nevertheless, how miR-140-5p regulates insulin resistance remains unclear. In this research, we aim to investigate the roles of miR-140-5p in insulin resistance. Methods qRT-PCR is used to analyze the expression level of miR-140-5p in insulin-resistant HepG2 cells. Glucose consumption and glucose uptake are detected to study the effect of miR-140-5p knockdown in insulin-resistant HepG2 cells and miR-140-5p overexpression in HepG2 cells. Bioinformatic analysis, luciferase reporter assay and confirmatory experiments are applied to identify the target gene bound with miR-140-5p and study the effect of miR-140-5p on the downstream substrates of target genes. Rescue experiments have verified the roles of miR-140-5p and target gene in glucose metabolism. Results The expression level of miR-140-5p was upregulated in insulin-resistant HepG2 cells and was significantly correlated with cellular glucose metabolism. Functionally, miR-140-5p overexpression induced impairment of glucose consumption and glucose uptake. Besides, bioinformatics analysis indicated that glycogen synthetase (GYS1) and protein phosphatase 1 catalytic subunit gamma (PPP1CC) were the target genes of miR-140-5p. Western blotting and qRT-PCR results revealed a negative correlation between GYS1, PPP1CC and miR-140-5p. The glycogen detection results showed that miR140-5p inhibited the production of the downstream substrates of the target gene. Rescue experiments showed that inhibition of GYS1 or PPP1CC partially enhanced the insulin-resistant effects of miR-140-5p knockdown in insulin-resistant HepG2 cells. Conclusion miR-140-5p overexpression augments the development of insulin resistance and miR-140-5p may be served as a therapeutic target of metabolic diseases.

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Section: Discussionmentioning

confidence: 99%

miR-140-5p Aggravates Insulin Resistance via Directly Targeting GYS1 and PPP1CC in Insulin-Resistant HepG2 Cells

Yan

Wang

et al. 2021

DMSO

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“…This was confirmed in LD mouse models. Down-regulating GS was achieved with (1) crosses between LD models and mice deficient of GS or proteins that activate this enzyme [87][88][89][90]; (2) delivering Gys1 targeting CRISPR/Cas9 to the brain with AAV9 [91] and (3) antisense oligonucleotides (ASO) against GS gene [92]. In all cases, PBs were drastically reduced and consequent neuropathological and behavioral phenotypes improved.…”

Section: Glycogen Synthase Reduction Therapymentioning

confidence: 99%

LUBAC: a new player in polyglucosan body disease

Aboujaoude

Minassian

Mitra

2021

Biochemical Society Transactions

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Altered protein ubiquitination is associated with the pathobiology of numerous diseases; however, its involvement in glycogen metabolism and associated polyglucosan body (PB) disease has not been investigated in depth. In PB disease, excessively long and less branched glycogen chains (polyglucosan bodies, PBs) are formed, which precipitate in different tissues causing myopathy, cardiomyopathy and/or neurodegeneration. Linear ubiquitin chain assembly complex (LUBAC) is a multi-protein complex composed of two E3 ubiquitin ligases HOIL-1L and HOIP and an adaptor protein SHARPIN. Together they are responsible for M1-linked ubiquitination of substrates primarily related to immune signaling and cell death pathways. Consequently, severe immunodeficiency is a hallmark of many LUBAC deficient patients. Remarkably, all HOIL-1L deficient patients exhibit accumulation of PBs in different organs especially skeletal and cardiac muscle resulting in myopathy and cardiomyopathy with heart failure. This emphasizes LUBAC's important role in glycogen metabolism. To date, neither a glycogen metabolism-related LUBAC substrate nor the molecular mechanism are known. Hence, current reviews on LUBAC's involvement in glycogen metabolism are lacking. Here, we aim to fill this gap by describing LUBAC's involvement in PB disease. We present a comprehensive review of LUBAC structure, its role in M1-linked and other types of atypical ubiquitination, PB pathology in human patients and findings in new mouse models to study the disease. We conclude the review with recent drug developments and near-future gene-based therapeutic approaches to treat LUBAC related PB disease.

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“…Degradation of pre‐existing PG and glycogen (PG precursor), on the other hand, as done by 144DG11, is a more direct target and is expected to be more efficacious than inhibition of de novo PG formation, as done by the GYS inhibitor guaiacol (Kakhlon et al , 2018), which spares pre‐made detrimental PG. Indeed, in a study in LD‐modeling mice, it was shown that conditional GYS knockdown after disease onset is unable to clear pre‐existing and detrimental Lafora PG bodies (Nitschke et al , 2021).…”

Section: Discussionmentioning

confidence: 99%

Alleviation of a polyglucosan storage disorder by enhancement of autophagic glycogen catabolism

et al. 2021

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This work employs adult polyglucosan body disease (APBD) models to explore the efficacy and mechanism of action of the polyglucosan‐reducing compound 144DG11. APBD is a glycogen storage disorder (GSD) caused by glycogen branching enzyme (GBE) deficiency causing accumulation of poorly branched glycogen inclusions called polyglucosans. 144DG11 improved survival and motor parameters in a GBE knockin (Gbeys/ys) APBD mouse model. 144DG11 reduced polyglucosan and glycogen in brain, liver, heart, and peripheral nerve. Indirect calorimetry experiments revealed that 144DG11 increases carbohydrate burn at the expense of fat burn, suggesting metabolic mobilization of pathogenic polyglucosan. At the cellular level, 144DG11 increased glycolytic, mitochondrial, and total ATP production. The molecular target of 144DG11 is the lysosomal membrane protein LAMP1, whose interaction with the compound, similar to LAMP1 knockdown, enhanced autolysosomal degradation of glycogen and lysosomal acidification. 144DG11 also enhanced mitochondrial activity and modulated lysosomal features as revealed by bioenergetic, image‐based phenotyping and proteomics analyses. As an effective lysosomal targeting therapy in a GSD model, 144DG11 could be developed into a safe and efficacious glycogen and lysosomal storage disease therapy.

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An inducible glycogen synthase-1 knockout halts but does not reverse Lafora disease progression in mice

Cited by 25 publications

References 48 publications

miR-140-5p Aggravates Insulin Resistance via Directly Targeting GYS1 and PPP1CC in Insulin-Resistant HepG2 Cells

miR-140-5p Aggravates Insulin Resistance via Directly Targeting GYS1 and PPP1CC in Insulin-Resistant HepG2 Cells

LUBAC: a new player in polyglucosan body disease

Alleviation of a polyglucosan storage disorder by enhancement of autophagic glycogen catabolism

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