PMID- 11102510
OWN - NLM
STAT- MEDLINE
DCOM- 20010208
LR  - 20181113
IS  - 1059-1524 (Print)
IS  - 1059-1524 (Linking)
VI  - 11
IP  - 12
DP  - 2000 Dec
TI  - Distinct FTDP-17 missense mutations in tau produce tau aggregates and other 
      pathological phenotypes in transfected CHO cells.
PG  - 4093-104
AB  - 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.
FAU - Vogelsberg-Ragaglia, V
AU  - Vogelsberg-Ragaglia V
AD  - The Center for Neurodegenerative Disease Research, Department of Pathology and 
      Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 
      19104, USA.
FAU - Bruce, J
AU  - Bruce J
FAU - Richter-Landsberg, C
AU  - Richter-Landsberg C
FAU - Zhang, B
AU  - Zhang B
FAU - Hong, M
AU  - Hong M
FAU - Trojanowski, J Q
AU  - Trojanowski JQ
FAU - Lee, V M
AU  - Lee VM
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Mol Biol Cell
JT  - Molecular biology of the cell
JID - 9201390
RN  - 0 (Protein Isoforms)
RN  - 0 (tau Proteins)
RN  - 17885-08-4 (Phosphoserine)
RN  - EC 3.4.- (Peptide Hydrolases)
SB  - IM
MH  - Animals
MH  - CHO Cells
MH  - Cricetinae
MH  - Dementia/genetics/pathology
MH  - Electrophoresis, Polyacrylamide Gel
MH  - Fluorescent Antibody Technique, Indirect
MH  - Microscopy, Electron
MH  - Microtubules/metabolism
MH  - Mutagenesis, Site-Directed
MH  - *Mutation, Missense
MH  - Parkinson Disease/genetics/pathology
MH  - Peptide Hydrolases/chemistry
MH  - Phenotype
MH  - Phosphorylation
MH  - Phosphoserine/metabolism
MH  - Protein Isoforms/genetics/metabolism
MH  - Solubility
MH  - Transfection
MH  - tau Proteins/*genetics/immunology/*metabolism
PMC - PMC15059
EDAT- 2000/12/05 11:00
MHDA- 2001/03/03 10:01
CRDT- 2000/12/05 11:00
PHST- 2000/12/05 11:00 [pubmed]
PHST- 2001/03/03 10:01 [medline]
PHST- 2000/12/05 11:00 [entrez]
AID - 1373 [pii]
AID - 10.1091/mbc.11.12.4093 [doi]
PST - ppublish
SO  - Mol Biol Cell. 2000 Dec;11(12):4093-104. doi: 10.1091/mbc.11.12.4093.