Linked Life Data

20858601

Source:http://linkedlifedata.com/resource/pubmed/id/20858601

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
23
pubmed:dateCreated
2010-11-5
pubmed:abstractText
Lafora disease (LD) is an autosomal recessive progressive myoclonic epilepsy characterized by the presence of intracellular polyglucosan inclusions commonly known as Lafora bodies in many tissues, including the brain, liver and skin. The disease is caused by mutations in either EPM2A gene, encoding the protein phosphatase, laforin, or EPM2B gene, encoding the ubiquitin ligase, malin. But how mutations in these two genes cause disease pathogenesis is poorly understood. In this study, we show that the Lafora bodies in the axillary skin and brain stain positively for the ubiquitin, the 20S proteasome and the molecular chaperones Hsp70/Hsc70. Interestingly, mutant malins that are misfolded also frequently colocalizes with Lafora bodies in the skin biopsy sample of the respective LD patient. The expression of disease-causing mutations of malin in Cos-7 cells results in the formation of the profuse cytoplasmic aggregates that colocalize with the Hsp70/Hsc70 chaperones and the 20S proteasome. The mutant malin expressing cells also exhibit proteasomal dysfunction and cell death. Overexpression of Hsp70 decreases the frequency of the mutant malin aggregation and protects from mutant malin-induced cell death. These findings suggest that Lafora bodies consist of abnormal proteins, including mutant malin, targeted by the chaperones or the proteasome for their refolding or clearance, and failure of these quality control systems could lead to LD pathogenesis. Our data also indicate that the Hsp70 chaperone could be a potential therapeutic target of LD.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Dec
pubmed:issn
1460-2083
pubmed:author
pubmed:issnType
Electronic
pubmed:day
1
pubmed:volume
19
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
4726-34
pubmed:meshHeading
pubmed:year
2010
pubmed:articleTitle
Sequestration of chaperones and proteasome into Lafora bodies and proteasomal dysfunction induced by Lafora disease-associated mutations of malin.
pubmed:affiliation
Cellular and Molecular Neuroscience Laboratory, National Brain Research Centre, Manesar, Gurgaon, India.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't