Abstract
In Alzheimer disease (AD), frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) and other tauopathies, tau accumulates and forms paired helical filaments (PHFs) in the brain. Tau isolated from PHFs is phosphorylated at a number of sites, migrates as approximately 60-, 64-, and 68-kDa bands on SDS-gel, and does not promote microtubule assembly. Upon dephosphorylation, the PHF-tau migrates as approximately 50-60-kDa bands on SDS-gels in a manner similar to tau that is isolated from normal brain and promotes microtubule assembly. The site(s) that inhibits microtubule assembly-promoting activity when phosphorylated in the diseased brain is not known. In this study, when tau was phosphorylated by Cdk5 in vitro, its mobility shifted from approximately 60-kDa bands to approximately 64- and 68-kDa bands in a time-dependent manner. This mobility shift correlated with phosphorylation at Ser(202), and Ser(202) phosphorylation inhibited tau microtubule-assembly promoting activity. When several tau point mutants were analyzed, G272V, P301L, V337M, and R406W mutations associated with FTDP-17, but not nonspecific mutations S214A and S262A, promoted Ser(202) phosphorylation and mobility shift to a approximately 68-kDa band. Furthermore, Ser(202) phosphorylation inhibited the microtubule assembly-promoting activity of FTDP-17 mutants more than of WT. Our data indicate that FTDP-17 missense mutations, by promoting phosphorylation at Ser(202), inhibit the microtubule assembly-promoting activity of tau in vitro, suggesting that Ser(202) phosphorylation plays a major role in the development of NFT pathology in AD and related tauopathies.
Highlights
Neurofibrillary tangles (NFTs)4 and senile plaques are the two characteristic neuropathological lesions found in the brains of patients suffering from Alzheimer disease (AD)
The presence of ϳ64- and 68-kDa tau bands is a characteristic feature of the AD brain, and studies suggest that the appearance of these species correlates with the disease progression [12, 13]
Because these tau species are formed due to abnormal tau phosphorylation, tau sites that are responsible for causing their formation are suggested to be involved in the development of AD pathology in brain [12, 13]
Summary
Neurofibrillary tangles (NFTs) and senile plaques are the two characteristic neuropathological lesions found in the brains of patients suffering from Alzheimer disease (AD). Tau hyperphosphorylation is suggested to cause microtubule instability and PHF formation, leading to NFT pathology in the brain [1,2,3]. Some sites are only partially phosphorylated in PHFs [8], whereas phosphorylation on specific sites inhibits the microtubule assembly-promoting activity of tau [6, 10] These observations suggest that phosphorylation on a few sites may be responsible and sufficient for causing tau dysfunction in AD. Tau sites involved in the tau mobility shift to ϳ64- and 68-kDa bands were suggested to have a role in AD pathology [12, 13]. Phosphorylation of FTDP-17 Tau Mutants mobility shift Identification of such sites will significantly enhance our knowledge of how NFT pathology develops in the brain
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