Targeting Pathogenic Lafora Bodies in Lafora Disease Using an Antibody-Enzyme Fusion

Brewer, M. Kathryn; Uittenbogaard, Annette; Austin, Grant L.; Segvich, Dyann M.; DePaoli‐Roach, Anna A.; Roach, Peter J.; McCarthy, John J.; Simmons, Zoe R.; Brandon, J. Anthony; Zhou, Zhengqiu; Zeller, Jill; Young, Lyndsay E.A.; Sun, Ramon C.; Pauly, James R.; Aziz, Nadine M.; Hodges, Bradley L.; McKnight, Tracy R.; Armstrong, Dustin D.; Gentry, Matthew S.

doi:10.1016/j.cmet.2019.07.002

Cited by 71 publications

(68 citation statements)

References 124 publications

(187 reference statements)

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“…To date, four therapeutic approaches are being developed to treat LD (for the latest update see Gentry et al, 2020). These include the use of antisense oligonucleotides targeting glycogen synthase to avoid the formation of Lafora bodies, enzyme therapy directed to degrade them once formed (Brewer et al, 2019), the use of smallmolecule inhibitors of glycogen synthase (Tang et al, 2020), and the use of repurposing drugs such as metformin (Berthier et al, 2016), although none of them have been translated to the clinic yet. It is therefore of great importance to continue investigating the molecular mechanisms of the disease to find a good therapeutic target and an effective treatment that could be used in clinical trials.…”

Section: Discussionmentioning

confidence: 99%

Endocytosis of the glutamate transporter 1 is regulated by laforin and malin: Implications in Lafora disease

Pérez-Jiménez

Viana

Muñoz‐Ballester

et al. 2020

Glia

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Lafora disease (LD) is a fatal rare type of progressive myoclonus epilepsy that appears during early adolescence. The disease is caused by mutations in EPM2A or EPM2B genes, which encode laforin, a glucan phosphatase, and malin, an E3‐ubiquitin ligase, respectively. Although the exact roles of laforin and malin are still not well understood, it is known that they work as a complex in which laforin recruits targets that will be ubiquitinated by malin. Recently, we suggested that the type of epilepsy that accompanies LD could be due to deficiencies in the function of the astrocytic glutamate transporter GLT‐1. We described that astrocytes from LD mouse models presented decreased levels of GLT‐1 at the plasma membrane, leading to increased levels of glutamate in the brain parenchyma. In this work, we present evidence indicating that in the absence of a functional laforin/malin complex (as in LD cellular models) there is an alteration in the ubiquitination of GLT‐1, which could be the cause of the reduction in the levels of GLT‐1 at the plasma membrane. On the contrary, overexpression of the laforin/malin complex promotes the retention of GLT‐1 at the plasma membrane. This retention may be due to the direct ubiquitination of GLT‐1 and/or to an opposite effect of this complex on the dynamics of the Nedd4.2‐mediated endocytosis of the transporter. This work, therefore, presents new pieces of evidence on the regulation of GLT‐1 by the laforin/malin complex, highlighting its value as a therapeutic target for the amelioration of the type of epilepsy that accompanies LD.

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Section: Discussionmentioning

confidence: 99%

Endocytosis of the glutamate transporter 1 is regulated by laforin and malin: Implications in Lafora disease

Pérez-Jiménez

Viana

Muñoz‐Ballester

et al. 2020

Glia

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“…GCMS (Agilent Technologies, Santa Clara, CA, USA) protocols were similar to those described previously [ 48 , 49 ] except a modified temperature gradient was used for GC: Initial temperature was 130 °C, held for 4 min, rising at 6 °C/min to 243 °C, rising at 60 °C/min to 280 °C, held for 2 min. The electron ionization (EI) energy was set to 70 eV.…”

Section: Methodsmentioning

confidence: 99%

Oral Gavage Delivery of Stable Isotope Tracer for In Vivo Metabolomics

et al. 2020

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Stable isotope-resolved metabolomics (SIRM) is a powerful tool for understanding disease. Advances in SIRM techniques have improved isotopic delivery and expanded the workflow from exclusively in vitro applications to in vivo methodologies to study systemic metabolism. Here, we report a simple, minimally-invasive and cost-effective method of tracer delivery to study SIRM in vivo in laboratory mice. Following a brief fasting period, we orally administered a solution of [U-13C] glucose through a blunt gavage needle without anesthesia, at a physiological dose commonly used for glucose tolerance tests (2 g/kg bodyweight). We defined isotopic enrichment in plasma and tissue at 15, 30, 120, and 240 min post-gavage. 13C-labeled glucose peaked in plasma around 15 min post-gavage, followed by period of metabolic decay and clearance until 4 h. We demonstrate robust enrichment of a variety of central carbon metabolites in the plasma, brain and liver of C57/BL6 mice, including amino acids, neurotransmitters, and glycolytic and tricarboxylic acid (TCA) cycle intermediates. We then applied this method to study in vivo metabolism in two distinct mouse models of diseases known to involve dysregulation of glucose metabolism: Alzheimer’s disease and type II diabetes. By delivering [U-13C] glucose via oral gavage to the 5XFAD Alzheimer’s disease model and the Lepob/ob type II diabetes model, we were able to resolve significant differences in multiple central carbon pathways in both model systems, thus providing evidence of the utility of this method to study diseases with metabolic components. Together, these data clearly demonstrate the efficacy and efficiency of an oral gavage delivery method, and present a clear time course for 13C enrichment in plasma, liver and brain of mice following oral gavage of [U-13C] glucose—data we hope will aid other researchers in their own 13C-glucose metabolomics study design.

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“…Quality of life should also be considered in switching to a restrictive diet with an as yet unproven benefit. Multiple emerging precision therapies offer hope for upcoming clinical trial recruitment including adeno-associated virus (AAV)-mediated replacement of EPM2A or NHLRC1 3 to rescue haploinsufficiency, fusion of a cell-penetrating antibody to pancreatic α-amylase which digests Lafora bodies (VAL-0417) 8 , and an antisense oligonucleotide (ASO) for PTG, a glycogen synthesis activator, to limit Lafora body production 9 .…”

Section: A C C E P T E Dmentioning

confidence: 99%

Pearls & Oy-sters: When Genetic Generalized Epilepsy Becomes Progressive

et al. 2021

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Targeting Pathogenic Lafora Bodies in Lafora Disease Using an Antibody-Enzyme Fusion

Abstract: Targeting Pathogenic Lafora Bodies in Lafora Disease Using an Antibody-Enzyme Fusion Notes/Citation Information To be published in Cell Metabolism.

Cited by 71 publications

References 124 publications

Endocytosis of the glutamate transporter 1 is regulated by laforin and malin: Implications in Lafora disease

Endocytosis of the glutamate transporter 1 is regulated by laforin and malin: Implications in Lafora disease

Oral Gavage Delivery of Stable Isotope Tracer for In Vivo Metabolomics

Pearls & Oy-sters: When Genetic Generalized Epilepsy Becomes Progressive

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