Laforin prevents stress-induced polyglucosan body formation and lafora disease progression in neurons

Yan Liu, Yin Wang, Keli Ma, Peixiang Wang, Otto Baba, Helen Zhang, Jack M. Parent, Pan Zheng, Yang Liu, Berge A. Minassian

Research output: Contribution to journalReview article

11 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)49-61
Number of pages13
JournalMolecular Neurobiology
Volume48
Issue number1
DOIs
StatePublished - Aug 1 2013

Fingerprint

Lafora Disease
Disease Progression
Glycogen
Neurons
Glycogen Phosphorylase
Glycogen Synthase
Glucose-6-Phosphate
Endoplasmic Reticulum Stress
Epilepsy
Seizures
polyglucosan
Apoptosis
Muscles
Brain
Enzymes
Proteins

Keywords

  • ER stress
  • Lafora body
  • Lafora disease
  • Laforin
  • Muscle glycogen synthase
  • Neurodegeneration
  • Neuron
  • Polyglucosan

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

Cite this

Laforin prevents stress-induced polyglucosan body formation and lafora disease progression in neurons. / Liu, Yan; Wang, Yin; Ma, Keli; Wang, Peixiang; Baba, Otto; Zhang, Helen; Parent, Jack M.; Zheng, Pan; Liu, Yang; Minassian, Berge A.

In: Molecular Neurobiology, Vol. 48, No. 1, 01.08.2013, p. 49-61.

Research output: Contribution to journalReview article

Liu, Y, Wang, Y, Ma, K, Wang, P, Baba, O, Zhang, H, Parent, JM, Zheng, P, Liu, Y & Minassian, BA 2013, 'Laforin prevents stress-induced polyglucosan body formation and lafora disease progression in neurons', Molecular Neurobiology, vol. 48, no. 1, pp. 49-61. https://doi.org/10.1007/s12035-013-8438-2
Liu, Yan ; Wang, Yin ; Ma, Keli ; Wang, Peixiang ; Baba, Otto ; Zhang, Helen ; Parent, Jack M. ; Zheng, Pan ; Liu, Yang ; Minassian, Berge A. / Laforin prevents stress-induced polyglucosan body formation and lafora disease progression in neurons. In: Molecular Neurobiology. 2013 ; Vol. 48, No. 1. pp. 49-61.
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AB - 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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