Linked Life Data

15090543

Source:http://linkedlifedata.com/resource/pubmed/id/15090543

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
27
pubmed:dateCreated
2004-6-28
pubmed:abstractText
The dementia familial encephalopathy with neuroserpin inclusion bodies (FENIB) is caused by the accumulation of mutant neuroserpin within neurons (Davis, R. L., Shrimpton, A. E., Holohan, P. D., Bradshaw, C., Feiglin, D., Sonderegger, P., Kinter, J., Becker, L. M., Lacbawan, F., Krasnewich, D., Muenke, M., Lawrence, D. A., Yerby, M. S., Shaw, C.-M., Gooptu, B., Elliott, P. R., Finch, J. T., Carrell, R. W., and Lomas, D. A. (1999) Nature 401, 376-379), but little is known about the trafficking of wild type and mutant neuroserpins. We have established a cell model to study the processing of wild type neuroserpin and the Syracuse (S49P) and Portland (S52R) mutants that cause FENIB. Here we show that Syracuse and Portland neuroserpin are retained soon after their synthesis in the endoplasmic reticulum and that the limiting step in their processing is the transport to the Golgi complex. This is in contrast to the wild type protein, which is secreted into the culture medium. Mutant neuroserpin is retained within the endoplasmic reticulum as polymers, similar to those isolated from the intraneuronal inclusions in the brains of individuals with FENIB. Remarkably, the Portland mutant showed faster accumulation and slower secretion compared with the Syracuse mutant, in keeping with the more severe clinical phenotype found in patients with the Portland variant of neuroserpin. Both mutant and wild type neuroserpin were partially degraded by proteasomes. Taken together, our results provide further understanding of how cells handle defective but ordered mutant proteins and provide strong support for a common mechanism of disease caused by mutants of the serine protease inhibitor superfamily.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jul
pubmed:issn
0021-9258
pubmed:author
pubmed:issnType
Print
pubmed:day
2
pubmed:volume
279
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
28283-91
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed-meshheading:15090543-Animals, pubmed-meshheading:15090543-Blotting, Western, pubmed-meshheading:15090543-COS Cells, pubmed-meshheading:15090543-Cysteine Endopeptidases, pubmed-meshheading:15090543-DNA, pubmed-meshheading:15090543-Dementia, pubmed-meshheading:15090543-Electrophoresis, Polyacrylamide Gel, pubmed-meshheading:15090543-Endoplasmic Reticulum, pubmed-meshheading:15090543-Enzyme Inhibitors, pubmed-meshheading:15090543-Glycoside Hydrolases, pubmed-meshheading:15090543-Golgi Apparatus, pubmed-meshheading:15090543-Humans, pubmed-meshheading:15090543-Immunohistochemistry, pubmed-meshheading:15090543-Microscopy, Fluorescence, pubmed-meshheading:15090543-Multienzyme Complexes, pubmed-meshheading:15090543-Mutation, pubmed-meshheading:15090543-Neurons, pubmed-meshheading:15090543-Neuropeptides, pubmed-meshheading:15090543-Phenotype, pubmed-meshheading:15090543-Plasmids, pubmed-meshheading:15090543-Polymers, pubmed-meshheading:15090543-Precipitin Tests, pubmed-meshheading:15090543-Proteasome Endopeptidase Complex, pubmed-meshheading:15090543-Serpins, pubmed-meshheading:15090543-Time Factors, pubmed-meshheading:15090543-Transfection
pubmed:year
2004
pubmed:articleTitle
Mutants of neuroserpin that cause dementia accumulate as polymers within the endoplasmic reticulum.
pubmed:affiliation
Departments of Medicine and Clinical Biochemistry, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust/Medical Research Council Building, Hills Road, Cambridge CB2 2XY, United Kingdom. em285@cam.ac.uk
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't