Document Detail


Laforin is required for the functional activation of malin in endoplasmic reticulum stress resistance in neuronal cells.
MedLine Citation:
PMID:  22578008     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Mutations in either EPM2A, the gene encoding a dual-specificity phosphatase named laforin, or NHLRC1, the gene encoding an E3 ubiquitin ligase named malin, cause Lafora disease in humans. Lafora disease is a fatal neurological disorder characterized by progressive myoclonus epilepsy, severe neurological deterioration and accumulation of poorly branched glycogen inclusions, called Lafora bodies or polyglucosan bodies, within the cell cytoplasm. The molecular mechanism underlying the neuropathogenesis of Lafora disease remains unknown. Here, we present data demonstrating that in the cells expressing low levels of laforin protein, overexpressed malin and its Lafora disease-causing missense mutants are stably polyubiquitinated. Malin and malin mutants form ubiquitin-positive aggregates in or around the nuclei of the cells in which they are expressed. Neither wild-type malin nor its mutants elicit endoplasmic reticulum stress, although the mutants exaggerate the response to endoplasmic reticulum stress. Overexpressed laforin impairs the polyubiquitination of malin while it recruits malin to polyglucosan bodies. The recruitment and activities of laforin and malin are both required for the polyglucosan body disruption. Consistently, targeted deletion of laforin in brain cells from Epm2a knockout mice increases polyubiquitinated proteins. Knockdown of Epm2a or Nhlrc1 in neuronal Neuro2a cells shows that they cooperate to allow cells to resist ER stress and apoptosis. These results reveal that a functional laforin-malin complex plays a critical role in disrupting Lafora bodies and relieving ER stress, implying that a causative pathogenic mechanism underlies their deficiency in Lafora disease.
Authors:
Li Zeng; Yin Wang; Otto Baba; Pan Zheng; Yang Liu; Yan Liu
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2012-06-08
Journal Detail:
Title:  The FEBS journal     Volume:  279     ISSN:  1742-4658     ISO Abbreviation:  FEBS J.     Publication Date:  2012 Jul 
Date Detail:
Created Date:  2012-07-03     Completed Date:  2012-10-08     Revised Date:  2013-07-03    
Medline Journal Info:
Nlm Unique ID:  101229646     Medline TA:  FEBS J     Country:  England    
Other Details:
Languages:  eng     Pagination:  2467-78     Citation Subset:  IM    
Copyright Information:
© 2012 The Authors Journal compilation © 2012 FEBS.
Affiliation:
Department of Surgery, University of Michigan Medical Center, Ann Arbor, MI 48109, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Blotting, Western
Cell Line, Tumor
Dual-Specificity Phosphatases / genetics,  metabolism*
Endoplasmic Reticulum Stress*
Female
Glucans / metabolism
HEK293 Cells
Humans
Immunoprecipitation
Inclusion Bodies / genetics,  metabolism
Lafora Disease / genetics,  metabolism
Male
Mice
Mice, 129 Strain
Mice, Inbred C57BL
Mice, Knockout
Mutation
Neurons / metabolism*
Polyubiquitin / metabolism
Protein Binding
Ubiquitin-Protein Ligases / genetics,  metabolism*
Grant Support
ID/Acronym/Agency:
1R21CA164469/CA/NCI NIH HHS; 1R21NS062391/NS/NINDS NIH HHS; R21 NS062391/NS/NINDS NIH HHS
Chemical
Reg. No./Substance:
0/Glucans; 120904-94-1/Polyubiquitin; 9012-72-0/polyglucosan; EC 3.1.3.48/Dual-Specificity Phosphatases; EC 3.1.3.48/Epm2a protein, mouse; EC 6.3.2.19/NHLRC1 protein, mouse; EC 6.3.2.19/Ubiquitin-Protein Ligases
Comments/Corrections

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