title: 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.affiliation: Section of General Surgery, Department of Surgery, University of Michigan Medical Center, Ann Arbor, MI 48109, USA.
authors.forename: Yin
authors.initials: Y
authors.lastname: Wang
authors.forename: Keli
authors.initials: K
authors.lastname: Ma
authors.forename: Peixiang
authors.initials: P
authors.lastname: Wang
authors.forename: Otto
authors.initials: O
authors.lastname: Baba
authors.forename: Helen
authors.initials: H
authors.lastname: Zhang
authors.forename: Jack M
authors.initials: JM
authors.lastname: Parent
authors.forename: Pan
authors.initials: P
authors.lastname: Zheng
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.forename: Berge A
authors.initials: BA
authors.lastname: Minassian
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D017209:Apoptosis; D018450:Disease Progression; D054637:Dual-Specificity Phosphatases / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress; D004789:Enzyme Activation; D055785:Gene Knockdown Techniques; D005936:Glucans / Q000378:metabolism*; D006003:Glycogen / Q000096:biosynthesis; D024981:Glycogen Phosphorylase / Q000378:metabolism; D006006:Glycogen Synthase / Q000378:metabolism; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D006868:Hydrolysis; D002479:Inclusion Bodies / Q000378:metabolism*; D020192:Lafora Disease / Q000201:enzymology / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009410:Nerve Degeneration / Q000201:enzymology / Q000473:pathology; D009474:Neurons / Q000201:enzymology / Q000473:pathology*; D010766:Phosphorylation; D054558:Protein Tyrosine Phosphatases, Non-Receptor; D000516:alpha-Amylases / Q000378:metabolism
chemical_list: D005936:Glucans; D006003:Glycogen; C083094:polyglucosan; D024981:Glycogen Phosphorylase; D006006:Glycogen Synthase; D054637:Dual-Specificity Phosphatases; C491989:Epm2a protein, mouse; D054558:Protein Tyrosine Phosphatases, Non-Receptor; D000516:alpha-Amylases
references.citation: Mol Biol Cell. 1994 Mar;5(3):253-65
references.pmid: 8049518
references.citation: J Biol Chem. 2012 Jul 20;287(30):25650-9
references.pmid: 22669944
references.citation: Mol Cell Biol. 2008 Dec;28(23):7236-44
references.pmid: 18824542
references.citation: Proc Natl Acad Sci U S A. 2005 Jun 14;102(24):8501-6
references.pmid: 15930137
references.citation: J Biol Chem. 1960 Apr;235:919-23
references.pmid: 14415527
references.citation: FEBS J. 2012 Jul;279(14):2467-78
references.pmid: 22578008
references.citation: Brain Res. 2005 Feb 21;1035(1):24-31
references.pmid: 15713273
references.citation: Nat Genet. 1998 Oct;20(2):171-4
references.pmid: 9771710
references.citation: Trends Pharmacol Sci. 1998 Apr;19(4):131-5
references.pmid: 9612087
references.citation: Anal Biochem. 1981 May 1;113(1):172-8
references.pmid: 7270882
references.citation: J Bacteriol. 1984 Dec;160(3):1027-30
references.pmid: 6501224
references.citation: J Biol Chem. 1958 Mar;231(1):259-75
references.pmid: 13538966
references.citation: Kokubyo Gakkai Zasshi. 1993 Jun;60(2):264-87
references.pmid: 8345245
references.citation: Anal Biochem. 1996 Sep 5;240(2):304-6
references.pmid: 8811927
references.citation: J Biol Chem. 2009 Aug 21;284(34):22657-63
references.pmid: 19542233
references.citation: Arch Neurol. 1971 Dec;25(6):483-93
references.pmid: 4329923
references.citation: Cell Metab. 2011 Mar 2;13(3):274-82
references.pmid: 21356517
references.citation: Nat Neurosci. 2007 Nov;10(11):1407-13
references.pmid: 17952067
references.citation: Cancer Cell. 2006 Sep;10(3):179-90
references.pmid: 16959610
references.citation: J Biol Chem. 2010 Aug 13;285(33):25372-81
references.pmid: 20538597
references.citation: Exp Mol Med. 2010 Nov 30;42(11):777-86
references.pmid: 20926918
references.citation: Hum Mol Genet. 2004 Jun 1;13(11):1117-29
references.pmid: 15102711
references.citation: Neurology. 1970 Feb;20(2):160-76
references.pmid: 4188951
references.citation: J Biol Chem. 2002 Jan 25;277(4):2377-80
references.pmid: 11739371
references.citation: Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19262-6
references.pmid: 18040046
references.citation: J Neurosci Res. 2003 Oct 15;74(2):179-83
references.pmid: 14515346
references.citation: J Clin Neurosci. 2005 Nov;12(8):911-4
references.pmid: 16246565
references.citation: J Biol Chem. 2006 Oct 13;281(41):30412-8
references.pmid: 16901901
references.citation: Brain Res. 2007 May 30;1150:55-61
references.pmid: 17397812
references.citation: Hum Mol Genet. 2009 Jul 15;18(14):2622-31
references.pmid: 19403557
references.citation: J Neurochem. 2004 May;89(3):537-52
references.pmid: 15086511
references.citation: Cancer Res. 2008 Jun 1;68(11):4039-44
references.pmid: 18519661
references.citation: Hum Mol Genet. 2002 May 15;11(11):1251-62
references.pmid: 12019206
references.citation: Electroencephalogr Clin Neurophysiol. 1972 Mar;32(3):281-94
references.pmid: 4110397
references.citation: EMBO Mol Med. 2011 Nov;3(11):667-81
references.pmid: 21882344
references.citation: J Biol Chem. 2008 Feb 15;283(7):4069-76
references.pmid: 18070875
references.citation: Acta Neuropathol. 1996 Nov;92(5):511-4
references.pmid: 8922063
references.citation: Adv Neurol. 2002;89:199-210
references.pmid: 11968446
references.citation: J Biol Chem. 2006 Nov 17;281(46):34768-74
references.pmid: 16971387
references.citation: Ann Neurol. 2010 Dec;68(6):925-33
references.pmid: 21077101
references.citation: J Biol Chem. 2008 Dec 5;283(49):33816-25
references.pmid: 18852261
references.citation: Hum Mol Genet. 2005 Sep 15;14(18):2727-36
references.pmid: 16115820
references.citation: Nat Genet. 2003 Oct;35(2):125-7
references.pmid: 12958597
references.citation: Brain Res Brain Res Rev. 1999 Apr;29(2-3):265-95
references.pmid: 10209236
references.citation: Neurology. 2006 Jan 24;66(2 Suppl 1):S102-9
references.pmid: 16432136