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Laforin Prevents Stress-Induced Polyglucosan Body Formation and Lafora Disease Progression in Neurons

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Abstract

Glycogen, the largest cytosolic macromolecule, is soluble because of intricate construction generating perfect hydrophilic-surfaced spheres. Little is known about neuronal glycogen function and metabolism, though progress is accruing through the neurodegenerative epilepsy Lafora disease (LD) proteins laforin and malin. Neurons in LD exhibit Lafora bodies (LBs), large accumulations of malconstructed insoluble glycogen (polyglucosans). We demonstrated that the laforin–malin complex reduces LBs and protects neuronal cells against endoplasmic reticulum stress-induced apoptosis. We now show that stress induces polyglucosan formation in normal neurons in culture and in the brain. This is mediated by increased glucose-6-phosphate allosterically hyperactivating muscle glycogen synthase (GS1) and is followed by activation of the glycogen digesting enzyme glycogen phosphorylase. In the absence of laforin, stress-induced polyglucosans are undigested and accumulate into massive LBs, and in laforin-deficient mice, stress drastically accelerates LB accumulation and LD. The mechanism through which laforin–malin mediates polyglucosan degradation remains unclear but involves GS1 dephosphorylation by laforin. Our work uncovers the presence of rapid polyglucosan metabolism as part of the normal physiology of neuroprotection. We propose that deficiency in the degradative phase of this metabolism, leading to LB accumulation and resultant seizure predisposition and neurodegeneration, underlies LD.

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Abbreviations

AMPK:

AMP-activated protein kinase

CBD:

Carbohydrate-binding domain

2-DG:

2-Deoxyglucose

ER:

Endoplasmic reticulum

G6P:

Glucose-6-phosphate

GDE1/AGL1:

Glycogen debranching enzyme 1

GSK3:

Glycogen synthase kinase 3

GPBB:

Glycogen phosphorylase isoenzyme BB

GS1:

Muscle glycogen synthase

LB:

Lafora body

LD:

Lafora disease

PB:

Polyglucosan body

N2A:

Neuro-2a

PAS:

Periodic acid-Schiff

PME:

Progressive myoclonic epilepsy

PTG:

Protein targeting to glycogen

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Acknowledgments

This work was supported by grants from the National Institutes of Health, 1R21NS062391 and 5R21CA164469, and the Canadian Institutes of Health Research to BAM. BAM holds the University of Toronto Michael Bahen chair in epilepsy research.

Conflict of Interest

The authors declare no competing financial interests.

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Authors and Affiliations

  1. Section of General Surgery, Department of Surgery, University of Michigan Medical Center, Ann Arbor, MI, 48109, USA

    Yin Wang, Keli Ma, Pan Zheng, Yang Liu & Yan Liu

  2. Department of Neurology, University of Michigan Medical Center, Ann Arbor, MI, 48109, USA

    Helen Zhang & Jack M. Parent

  3. Department of Pathology, University of Michigan Medical Center, Ann Arbor, MI, 48109, USA

    Pan Zheng

  4. Center for Cancer and Immunology, Children’s National Medical Center and George Washington University, Washington, DC, 20010, USA

    Yin Wang & Yan Liu

  5. Program in Genetics and Genome Biology, The Hospital for Sick Children and University of Toronto, Toronto, ON, Canada

    Peixiang Wang & Berge A. Minassian

  6. Department of Hard Tissue Engineering, Tokyo Medical and Dental University, Tokyo, Japan

    Otto Baba

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  1. Yin Wang
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Correspondence to Yan Liu.

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Wang, Y., Ma, K., Wang, P. et al. Laforin Prevents Stress-Induced Polyglucosan Body Formation and Lafora Disease Progression in Neurons. Mol Neurobiol 48, 49–61 (2013). https://doi.org/10.1007/s12035-013-8438-2

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