Familial FTDP-17 missense mutations inhibit microtubule assembly-promoting activity of tau by increasing phosphorylation at Ser202 in vitro.
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.
Han
Dong
D
Bloomfield Center for Research in Aging, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital McGill University, Montreal, Quebec H3T 1E2, Canada.
Qureshi
Hamid Y
HY
Bloomfield Center for Research in Aging, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital McGill University, Montreal, Quebec H3T 1E2, Canada.
Lu
Yifan
Y
Bloomfield Center for Research in Aging, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital McGill University, Montreal, Quebec H3T 1E2, Canada.
Paudel
Hemant K
HK
Bloomfield Center for Research in Aging, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital McGill University, Montreal, Quebec H3T 1E2, Canada; Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec H3T 1E2, Canada. Electronic address: hemant.paudel@mcgill.ca.
D000818:Animals; D002417:Cattle; D002886:Chromosomes, Human, Pair 17 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D051360:Cyclin-Dependent Kinase 5 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008870:Microtubules / Q000235:genetics; D020125:Mutation, Missense; D010766:Phosphorylation; D024801:Tauopathies / Q000235:genetics / Q000378:metabolism; D016875:tau Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
C054369:MAPT protein, human; D016875:tau Proteins; D051360:Cyclin-Dependent Kinase 5; C495905:CDK5 protein, human