Missense tau mutations identified in FTDP-17 have a small effect on tau-microtubule interactions.
Frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17) is a group of related disorders frequently characterized by the formation of tau inclusions in neurons and glial cells. To determine whether the formation of tau inclusions in FTDP-17 results from an alteration in the ability of mutant tau to maintain the microtubule (MT) system, we compared wild type four-repeat tau with three FTDP-17 mutants (P301L, V337M and R406W) for their ability to bind MT, promote MT assembly and bundling. According to in vitro binding and assembly assays, P301L is the only mutant that demonstrates a small, yet significant reduction, in its affinity for MT while both P301L and R406W have a small reduction in their ability to promote tubulin assembly. Based on studies of neuroblastoma and CHO cells transfected with GFP-tagged tau DNA constructs, both mutant and wild type tau transfectants were indistinguishable in the distribution pattern of tau in terms of co-localization with MT and generation of MT bundles. These results suggest that missense mutation of tau gene do not have an immediate impact on the integrity of MT system, and that exposure of affected neurons to additional insults or factors (e.g., aging) may be needed to initiate the formation of tau inclusions in FTDP-17.
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Departments of Pharmacology, Biochemistry and Molecular Biology, Birdsall Medical Research Building, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
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Yen
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Nacharaju
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Easson
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Lewis
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van Slegtenhorst
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Hutton
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Yen
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D000818:Animals; D002417:Cattle; D002460:Cell Line; D002474:Cell-Free System / Q000378:metabolism; D003704:Dementia / Q000235:genetics* / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D008854:Microscopy, Electron; D008870:Microtubules / Q000378:metabolism* / Q000648:ultrastructure; D020125:Mutation, Missense; D009447:Neuroblastoma / Q000378:metabolism / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D014404:Tubulin / Q000378:metabolism; D016875:tau Proteins / Q000235:genetics* / Q000378:metabolism*
D011994:Recombinant Proteins; D014404:Tubulin; D016875:tau Proteins; D017239:Paclitaxel