Deciphering the Polyglucosan Accumulation Present in Lafora Disease Using an Astrocytic Cellular Model

Moreno-Estellés, Mireia; Campos-Rodríguez, Ángela; Rubio-Villena, Carla; Kumarasinghe, Lorena; García-Gimeno, Maria Adelaida; Sanz, Pascual

doi:10.3390/ijms24076020

Cited by 3 publications

(1 citation statement)

References 46 publications

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“…In Lafora disease, caused by mutations in epilepsy progressive myoclonus type 2a ( EPM2A) and epilepsy progressive myoclonus type 2b ( EPM2B) genes, PGBs accumulate in many organs and tissues including the brain, skin, liver, heart, and skeletal muscle. Typically, this leads to ataxia and seizures in adolescence and the progressive development of severe dementia (Duran and Guinovart, 2015; Moreno-Estellés et al, 2023; Wang et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

ThePgb1locus controls glycogen aggregation in astrocytes of the aged hippocampus without impacting cognitive function

Gómez-Pascual,

Glikman,

et al. 2023

Preprint

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Aging can be associated with the accumulation of hypobranched glycogen molecules (polyglucosan bodies, PGBs), particularly in astrocytes of the hippocampus. While PGBs have a detrimental effect on cognition in diseases such as adult polyglucosan body disease and Lafora disease, the underlying mechanism and clinical relevance of age-related PGB accumulation remains unknown. Here, we have investigated the genetic basis and functional impact of age-related PGB accumulation in 32 fully sequenced BXD-type strains of mice which exhibit a 400-fold variation in PGB burden in 16-18 month old females. We mapped a major locus controlling PGB density in the hippocampus to chromosome 1 at 72–75 Mb (linkage of 4.9 –logP), which we defined as thePgb1locus. To identify potentially causal gene variants withinPgb1, we generated extensive hippocampal transcriptome datasets and identified two strong candidate genes for which mRNA correlates with PGB density—Smarcal1andUsp37. In addition, bothSmarcal1andUsp37contain non-synonymous allele variations likely to impact protein function. A phenome-wide association analysis highlighted a trans-regulatory effect of thePgb1locus on expression ofHp1bp3, a gene known to play a role in age-related changes in learning and memory. To investigate the potential impact of PGBs on cognition, we performed conditioned fear memory testing on strains displaying varying degrees of PGB burden, and a phenome-wide association scan of ~12,000 traits. Importantly, we did not find any evidence suggesting a negative impact of PGB burden on cognitive capacity. Taken together, we have identified a major modifier locus controlling PGB burden in the hippocampus and shed light on the genetic architecture and clinical relevance of this strikingly heterogeneous hippocampal phenotype.

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Section: Introductionmentioning

confidence: 99%

ThePgb1locus controls glycogen aggregation in astrocytes of the aged hippocampus without impacting cognitive function

Gómez-Pascual,

Glikman,

et al. 2023

Preprint

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1H and 31P magnetic resonance spectroscopy reveals potential pathogenic and biomarker metabolite alterations in Lafora disease

Chan,

Panatpur,

Messahel

et al. 2024

Brain Communications

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Lafora disease is a fatal teenage-onset progressive myoclonus-epilepsy and neurodegenerative disease associated with polyglucosan bodies. Polyglucosans are long-branched and as a result precipitation and aggregation-prone glycogen. In mouse models, downregulation of glycogen synthase, the enzyme that elongates glycogen branches, prevents polyglucosan formation and rescues Lafora disease. Mouse work, however, has not yet revealed the mechanisms of polyglucosan generation, and few in vivo human studies have been performed. Here, non-invasive in vivo magnetic resonance spectroscopy (1H and 31P) was applied to test scan feasibility, and assess neurotransmitter balance and energy metabolism in Lafora disease toward a better understanding of pathogenesis. Macromolecule-suppressed GABA-edited 1H magnetic resonance spectroscopy and 31P magnetic resonance spectroscopy at 3 Tesla and 7 Tesla, respectively, were performed in 4 Lafora disease patients and a total of 21 healthy controls (12 for the 1H- magnetic resonance spectroscopy and 9 for the 31P-magnetic resonance spectroscopy). Spectra were processed using in-house software and fit to extract metabolite concentrations. From the 1H spectra, we found 33% lower GABA concentrations (p = 0.013), 34% higher glutamate + glutamine concentrations (p = 0.011), and 24% lower N-acetylaspartate concentrations (p = 0.0043) in Lafora disease patients compared to controls. From the 31P spectra, we found 34% higher phosphoethanolamine concentrations (p = 0.016), 23% lower nicotinamide adenine dinucleotide concentrations (p = 0.003), 50% higher uridine diphosphate glucose concentrations (p = 0.004) and 225% higher glucose 6-phosphate concentrations in Lafora disease patients versus controls (p = 0.004). Uridine diphosphate glucose is the substrate of glycogen synthase and glucose 6-phosphate is its extremely potent allosteric activator. The observed elevated uridine diphosphate glucose and glucose 6-phosphate levels are expected to hyperactivate glycogen synthase and may underlie the generation of polyglucosans in Lafora disease. The increased glutamate + glutamine and reduced GABA indicate altered neurotransmission and energy metabolism, which may contribute to the disease’s intractable epilepsy. These results suggest a possible basis of polyglucosan formation and potential contributions to the epilepsy of Lafora disease. If confirmed in larger human and animal model studies, measurements of the dysregulated metabolites by magnetic resonance spectroscopy could be developed into non-invasive biomarkers for clinical trials.

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Glial alterations in the glutamatergic and GABAergic signaling pathways in a mouse model of Lafora disease, a severe form of progressive myoclonus epilepsy

Viana,

Rubio,

Campos-Rodríguez

et al. 2024

Preprint

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Lafora disease (LD; OMIM#254780) is a rare form of progressive myoclonus epilepsy characterized by the accumulation of insoluble deposits of aberrant glycogen (polyglucosans), named Lafora bodies (LBs), in the brain but also in peripheral tissues. It is assumed that the accumulation of LBs is related to the appearance of the characteristic pathological features of the disease. In mouse models of LD, we and others have reported an increase in the levels of reactive astrocytes and activated microglia, which triggers the expression of the different pro-inflammatory mediators. Recently, we have demonstrated that the TNF and IL-6 inflammatory signaling pathways are the main mediators of the neuroinflammatory phenotype associated with the disease. In this work, we present evidence that the activation of these pathways produces a dysregulation in the levels of different subunits of the excitatory ionotropic glutamatergic receptors (phopho-GluN2B, phospho-GluA2, GluK2) and also an increase in the levels of the GABA transporter GAT1 in the hippocampus of theEpm2b-/-mice. In addition, we present evidence of the presence of activated forms of the Src and Lyn protein kinases in this area. These effects may increase the excitatory glutamatergic signaling and decrease the inhibitory GABAergic tone, leading to hyper-excitability. More importantly, the enhanced production of these subunits occurs in non-neuronal cells such as activated microglia and reactive astrocytes, pointing out a key role of glia in the pathophysiology of LD.

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Deciphering the Polyglucosan Accumulation Present in Lafora Disease Using an Astrocytic Cellular Model

Cited by 3 publications

References 46 publications

ThePgb1locus controls glycogen aggregation in astrocytes of the aged hippocampus without impacting cognitive function

ThePgb1locus controls glycogen aggregation in astrocytes of the aged hippocampus without impacting cognitive function

1H and 31P magnetic resonance spectroscopy reveals potential pathogenic and biomarker metabolite alterations in Lafora disease

Glial alterations in the glutamatergic and GABAergic signaling pathways in a mouse model of Lafora disease, a severe form of progressive myoclonus epilepsy

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