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

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.

• Authors: Yin Wang, Keli Ma, Peixiang Wang, Otto Baba, Helen Zhang, Jack M Parent, Pan Zheng, Yang Liu, Berge A Minassian, Yan Liu
• Journal: Molecular neurobiology (Mol Neurobiol) Vol. 48 Issue 1 Pg. 49-61 (Aug 2013) ISSN: 1559-1182 [Electronic] United States
• PMID: 23546741 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Glucans
• Glycogen
• polyglucosan
• Glycogen Phosphorylase
• Glycogen Synthase
• Dual-Specificity Phosphatases
• Epm2a protein, mouse
• Protein Tyrosine Phosphatases, Non-Receptor
• alpha-Amylases

Topics

• Allosteric Regulation
• Animals
• Apoptosis
• Disease Progression
• Dual-Specificity Phosphatases (metabolism)
• Endoplasmic Reticulum Stress
• Enzyme Activation
• Gene Knockdown Techniques
• Glucans (metabolism)
• Glycogen (biosynthesis)
• Glycogen Phosphorylase (metabolism)
• Glycogen Synthase (metabolism)
• HEK293 Cells
• Hep G2 Cells
• Humans
• Hydrolysis
• Inclusion Bodies (metabolism)
• Lafora Disease (enzymology, pathology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Nerve Degeneration (enzymology, pathology)
• Neurons (enzymology, pathology)
• Phosphorylation
• Protein Tyrosine Phosphatases, Non-Receptor
• alpha-Amylases (metabolism)