Guaiacol as a drug candidate for treating adult polyglucosan body disease

Kakhlon, Or; Ferreira, Igor; Solmesky, Leonardo J.; Khazanov, Netaly; Lossos, Alexander; Álvarez, Rafael; Yetil, Deniz; Pampou, Sergey; Weil, Miguel; Senderowitz, Hanoch; Escribá, Pablo V.; Yue, Wyatt W.; Akman, Hasan O.

doi:10.1172/jci.insight.99694

Cited by 40 publications

(43 citation statements)

References 29 publications

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“…As PB quantity was not compared before and after treatment, it remains unclear whether the observed difference in PB quantity was exclusively due to treatment-dependent halting of PB formation or whether some form of polyglucosan degradation occurred. Nevertheless, it was shown that, in cell culture, guaiacol treatment was able to reduce glycogen that was deemed amylase resistant under the experimental conditions (Solmesky et al, 2017; Kakhlon et al, 2018). Whether this effect is attributable exclusively to GYS1 inhibition remains to be determined.…”

Section: Resultsmentioning

confidence: 98%

“…Treatment approaches aiming at lowering GYS1 activity globally would include a reduced formation of at risk sites as elongation:branching ratio is generally decreased. For instance, Gbe1 ys/ys mice treated for 12 months with GYS1 inhibitor guaiacol showed reduced polyglucosan bodies when compared to untreated animals (Kakhlon et al, 2018). As PB quantity was not compared before and after treatment, it remains unclear whether the observed difference in PB quantity was exclusively due to treatment-dependent halting of PB formation or whether some form of polyglucosan degradation occurred.…”

Section: Resultsmentioning

confidence: 99%

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Skeletal Muscle Glycogen Chain Length Correlates with Insolubility in Mouse Models of Polyglucosan-Associated Neurodegenerative Diseases

et al. 2019

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SUMMARY Lafora disease (LD) and adult polyglucosan body disease (APBD) are glycogen storage diseases characterized by a pathogenic buildup of insoluble glycogen. Mechanisms causing glycogen insolubility are poorly understood. Here, in two mouse models of LD (Epm2a−/− and Epm2b−/−) and one of APBD (Gbe1ys/ys), the separation of soluble and insoluble muscle glycogen is described, enabling separate analysis of each fraction. Total glycogen is increased in LD and APBD mice, which, together with abnormal chain length and molecule size distributions, is largely if not fully attributed to insoluble glycogen. Soluble glycogen consists of molecules with distinct chain length distributions and differential corresponding solubility, providing a mechanistic link between soluble and insoluble glycogen in vivo. Phosphorylation states differ across glycogen fractions and mouse models, demonstrating that hyperphosphorylation is not a basic feature of insoluble glycogen. Lastly, model-specific variances in protein and activity levels of key glycogen synthesis enzymes suggest uninvestigated regulatory mechanisms.

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Section: Resultsmentioning

confidence: 98%

Section: Resultsmentioning

confidence: 99%

Skeletal Muscle Glycogen Chain Length Correlates with Insolubility in Mouse Models of Polyglucosan-Associated Neurodegenerative Diseases

et al. 2019

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“…The anticipated safety profile of GYS1 knockdown is furthermore favorable as humans with one null GYS1 allele are healthy 34 . GYS1 could be downregulated at the DNA, RNA, or protein levels, and progress is already being made at least in the latter with promising compounds including guaiacol 35 and imidazole analogs 36 . PPP1R3C deficiency has to date not been associated with a pathological state in humans.…”

Section: Discussionmentioning

confidence: 99%

GYS1 or PPP1R3C deficiency rescues murine adult polyglucosan body disease

Chown

Wang

Zhao

et al. 2020

Ann Clin Transl Neurol

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Objective: Adult polyglucosan body disease (APBD) is an adult-onset neurological variant of glycogen storage disease type IV. APBD is caused by recessive mutations in the glycogen branching enzyme gene, and the consequent accumulation of poorly branched glycogen aggregates called polyglucosan bodies in the nervous system. There are presently no treatments for APBD. Here, we test whether downregulation of glycogen synthesis is therapeutic in a mouse model of the disease. Methods: We characterized the effects of knocking out two proglycogenic proteins in an APBD mouse model. APBD mice were crossed with mice deficient in glycogen synthase (GYS1), or mice deficient in protein phosphatase 1 regulatory subunit 3C (PPP1R3C), a protein involved in the activation of GYS1. Phenotypic and histological parameters were analyzed and glycogen was quantified. Results: APBD mice deficient in GYS1 or PPP1R3C demonstrated improvements in life span, morphology, and behavioral assays of neuromuscular function. Histological analysis revealed a reduction in polyglucosan body accumulation and of astro-and micro-gliosis in the brains of GYS1-and PPP1R3C-deficient APBD mice. Brain glycogen quantification confirmed the reduction in abnormal glycogen accumulation. Analysis of skeletal muscle, heart, and liver found that GYS1 deficiency reduced polyglucosan body accumulation in all three tissues and PPP1R3C knockout reduced skeletal muscle polyglucosan bodies. Interpretation: GYS1 and PPP1R3C are effective therapeutic targets in the APBD mouse model. These findings represent a critical step toward the development of a treatment for APBD and potentially other glycogen storage disease type IV patients.

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“…As in muscle, a pre-extraction incubation as devised removes all soluble and non-inert glycogen, revealing a very robust difference between diseased and WT animals already at a young age. As studies in young mice can be completed faster and therefore present a smaller financial burden, this method will be beneficial in studies assessing efficacy of therapeutic approaches for prevention or removal of insoluble brain glycogen, such as in LD (10,31) or adult polyglucosan body disease (41). The sensitivity of the described method is sufficient to determine inert αglucans in pieces of mouse brain weighing less than 20 mg, e.g.…”

Section: Quantification Of Inert α-Glucans In Hippocampi Of Ld Micementioning

confidence: 99%

“…Monitoring glycogen synthesis in human cell culture is crucial in any therapeutic study targeting central enzymes of glycogen metabolism. For instance, glycogen synthase has been identified a therapeutic target in LD (13,43,44) and adult polyglucosan body disease (41).…”

Section: Quantification Of α-Glucans In Hek293 Cells Cultured In 96 Wmentioning

confidence: 99%

Sensitive quantification of α-glucans in mouse tissues, cell cultures, and human cerebrospinal fluid

Nitschke

Petković

Ahonen

et al. 2020

Journal of Biological Chemistry

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The soluble α-polyglucan glycogen is a central metabolite enabling transient glucose storage to suit cellular energy needs. Glycogen storage diseases (GSDs) comprise over 15 entities caused by generalized or tissue-specific defects in enzymes of glycogen metabolism. In several, e.g. in Lafora disease caused by the absence of the glycogen phosphatase laforin or its interacting partner malin, degradation-resistant abnormally structured insoluble glycogen accumulates. Sensitive quantification methods for soluble and insoluble glycogen are critical to research, including therapeutic studies, in such diseases. This paper establishes methodological advancements relevant to glycogen metabolism investigations generally, and GSDs. Introducing a pre-extraction incubation method, we measure degradation-resistant glycogen in as little as 30 mg skeletal muscle or a single hippocampus from Lafora disease mouse models. The digestion-resistant glycogen correlates with the disease-pathogenic insoluble glycogen and can readily be detected in very young mice where glycogen accumulation has just begun. Secondly, we establish a high-sensitivity glucose assay with detection of ATP depletion, enabling 1) quantification of α-glucans in cell culture using a medium-throughput assay suitable for assessment of candidate glycogen synthesis inhibitors, and 2) discovery of α-glucan material in healthy human cerebrospinal fluid, establishing a novel methodological platform for biomarker analyses in Lafora disease and other GSDs.

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Guaiacol as a drug candidate for treating adult polyglucosan body disease

Cited by 40 publications

References 29 publications

Skeletal Muscle Glycogen Chain Length Correlates with Insolubility in Mouse Models of Polyglucosan-Associated Neurodegenerative Diseases

Skeletal Muscle Glycogen Chain Length Correlates with Insolubility in Mouse Models of Polyglucosan-Associated Neurodegenerative Diseases

GYS1 or PPP1R3C deficiency rescues murine adult polyglucosan body disease

Sensitive quantification of α-glucans in mouse tissues, cell cultures, and human cerebrospinal fluid

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