Tau mutations in frontotemporal dementia FTDP-17 and their relevance for Alzheimer's disease.
Alzheimer's disease is characterised by the degeneration of selected populations of nerve cells that develop filamentous inclusions prior to degeneration. The neuronal inclusions of Alzheimer's disease are made of the microtubule-associated protein tau, in a hyperphosphorylated state. Abundant filamentous tau inclusions are not limited to Alzheimer's disease. They are the defining neuropathological characteristic of frontotemporal dementias, such as Pick's disease, and of progressive supranuclear palsy and corticobasal degeneration. The discovery of mutations in the tau gene in familial frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) has provided a direct link between tau dysfunction and dementing disease. Known mutations produce either a reduced ability of tau to interact with microtubules, or an overproduction of tau isoforms with four microtubule-binding repeats. This leads in turn to the assembly of tau into filaments similar or identical to those found in Alzheimer's disease brain. Several missense mutations also have a stimulatory effect on heparin-induced tau filament formation. Assembly of tau into filaments may be the gain of toxic function that is believed to underlie the demise of affected brain cells.
Goedert
M
M
Medical Research Council Laboratory of Molecular Biology, Cambridge, UK. mg@mrc-lmb.cam.ac.uk
Spillantini
M G
MG
D017668:Age of Onset; D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology; D001921:Brain / Q000378:metabolism / Q000473:pathology; D003704:Dementia / Q000235:genetics* / Q000473:pathology; D005091:Exons; D006801:Humans; D007438:Introns; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D008870:Microtubules / Q000648:ultrastructure; D009154:Mutation; D010750:Phosphoproteins / Q000378:metabolism; D020033:Protein Isoforms / Q000378:metabolism; D016875:tau Proteins / Q000235:genetics* / Q000378:metabolism / Q000648:ultrastructure
C054369:MAPT protein, human; D008869:Microtubule-Associated Proteins; D010750:Phosphoproteins; D020033:Protein Isoforms; D016875:tau Proteins