PMID- 19304664
OWN - NLM
STAT- MEDLINE
DCOM- 20090630
LR  - 20211020
IS  - 0021-9258 (Print)
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Linking)
VI  - 284
IP  - 20
DP  - 2009 May 15
TI  - Familial FTDP-17 missense mutations inhibit microtubule assembly-promoting 
      activity of tau by increasing phosphorylation at Ser202 in vitro.
PG  - 13422-13433
LID - S0021-9258(20)58196-9 [pii]
LID - 10.1074/jbc.M901095200 [doi]
AB  - 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.
FAU - Han, Dong
AU  - Han D
AD  - 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.
FAU - Qureshi, Hamid Y
AU  - Qureshi HY
AD  - 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.
FAU - Lu, Yifan
AU  - Lu Y
AD  - 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.
FAU - Paudel, Hemant K
AU  - Paudel HK
AD  - 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.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20090319
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (MAPT protein, human)
RN  - 0 (tau Proteins)
RN  - EC 2.7.11.1 (Cyclin-Dependent Kinase 5)
RN  - EC 2.7.11.22 (CDK5 protein, human)
SB  - IM
MH  - Animals
MH  - Cattle
MH  - Chromosomes, Human, Pair 17/chemistry/genetics/metabolism
MH  - Cyclin-Dependent Kinase 5/chemistry/genetics/*metabolism
MH  - Humans
MH  - Microtubules/genetics
MH  - *Mutation, Missense
MH  - Phosphorylation
MH  - Tauopathies/genetics/metabolism
MH  - tau Proteins/chemistry/genetics/*metabolism
PMC - PMC2679442
EDAT- 2009/03/24 09:00
MHDA- 2009/07/01 09:00
PMCR- 2010/05/15
CRDT- 2009/03/24 09:00
PHST- 2009/03/24 09:00 [entrez]
PHST- 2009/03/24 09:00 [pubmed]
PHST- 2009/07/01 09:00 [medline]
PHST- 2010/05/15 00:00 [pmc-release]
AID - S0021-9258(20)58196-9 [pii]
AID - 13422 [pii]
AID - 10.1074/jbc.M901095200 [doi]
PST - ppublish
SO  - J Biol Chem. 2009 May 15;284(20):13422-13433. doi: 10.1074/jbc.M901095200. Epub 
      2009 Mar 19.