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PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
12
pubmed:dateCreated
2000-12-21
pubmed:abstractText
Multiple tau gene mutations are pathogenic for hereditary frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), with filamentous tau aggregates as the major lesions in the CNS of these patients. Recent studies have shown that bacterially expressed recombinant tau proteins with FTDP-17 missense mutations cause functional impairments, i.e., a reduced ability of mutant tau to bind to or promote the assembly of microtubules. To investigate the biological consequences of FTDP-17 tau mutants and assess their ability to form filamentous aggregates, we engineered Chinese hamster ovary cell lines to stably express tau harboring one or several different FTDP-17 mutations and showed that different tau mutants produced distinct pathological phenotypes. For example, delta K, but not several other single tau mutants (e.g., V337 M, P301L, R406W), developed insoluble amorphous and fibrillar aggregates, whereas a triple tau mutant (VPR) containing V337M, P301L, and R406W substitutions also formed similar aggregates. Furthermore, the aggregates increased in size over time in culture. Significantly, the formation of aggregated delta K and VPR tau protein correlated with reduced affinity of these mutants to bind microtubules. Reduced phosphorylation and altered proteolysis was also observed in R406W and delta K tau mutants. Thus, distinct pathological phenotypes, including the formation of insoluble filamentous tau aggregates, result from the expression of different FTDP-17 tau mutants in transfected Chinese hamster ovary cells and implies that these missense mutations cause diverse neurodegenerative FTDP-17 syndromes by multiple mechanisms.
pubmed:commentsCorrections
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pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Dec
pubmed:issn
1059-1524
pubmed:author
pubmed:issnType
Print
pubmed:volume
11
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
4093-104
pubmed:dateRevised
2009-11-18
pubmed:meshHeading
pubmed-meshheading:11102510-Animals, pubmed-meshheading:11102510-CHO Cells, pubmed-meshheading:11102510-Cricetinae, pubmed-meshheading:11102510-Dementia, pubmed-meshheading:11102510-Electrophoresis, Polyacrylamide Gel, pubmed-meshheading:11102510-Fluorescent Antibody Technique, Indirect, pubmed-meshheading:11102510-Microscopy, Electron, pubmed-meshheading:11102510-Microtubules, pubmed-meshheading:11102510-Mutagenesis, Site-Directed, pubmed-meshheading:11102510-Mutation, Missense, pubmed-meshheading:11102510-Parkinson Disease, pubmed-meshheading:11102510-Peptide Hydrolases, pubmed-meshheading:11102510-Phenotype, pubmed-meshheading:11102510-Phosphorylation, pubmed-meshheading:11102510-Phosphoserine, pubmed-meshheading:11102510-Protein Isoforms, pubmed-meshheading:11102510-Solubility, pubmed-meshheading:11102510-Transfection, pubmed-meshheading:11102510-tau Proteins
pubmed:year
2000
pubmed:articleTitle
Distinct FTDP-17 missense mutations in tau produce tau aggregates and other pathological phenotypes in transfected CHO cells.
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