Laforin is required for the functional activation of malin in endoplasmic reticulum stress resistance in neuronal cells.

The FEBS Journal
Li ZengYan Liu

Abstract

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, t...Continue Reading

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Citations

Jan 17, 2014·Brain : a Journal of Neurology·Javier GayarreSantiago Rodríguez de Córdoba
Feb 15, 2015·Free Radical Biology & Medicine·Carlos Romá-MateoFederico V Pallardó
Jun 24, 2015·Biochemical and Biophysical Research Communications·Mamta UpadhyaySubramaniam Ganesh
May 20, 2014·Molecular Neurobiology·Carlos Romá-MateoPascual Sanz
Jan 15, 2013·Seizure : the Journal of the British Epilepsy Association·Dimitrios ChatzistefanidisSofia Markoula
Feb 24, 2015·Frontiers in Neurology·Pankaj Kumar Singh, Sweta Singh

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