Document Detail


Cis phosphorylated tau as the earliest detectable pathogenic conformation in Alzheimer disease, offering novel diagnostic and therapeutic strategies.
MedLine Citation:
PMID:  23154634     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
After protein phosphorylation on certain serine or threonine residues preceding a proline (pSer/Thr-Pro), the function of certain phosphorylated protein is further regulated by cis-trans conformational change. Due to the lack of any tool to detect such two conformations in cells, however, it is not even known whether any cis or trans conformation exists in vivo, not to mention their conformation-specific functions or regulation. We developed a novel peptide chemistry technology to generate the first pair of antibodies that can distinguish cis from trans pThr231-Pro tau. Cis, but not trans, pThr231-tau appears early in mild cognitive impairment (MCI) neurons and further accumulates in only degenerating neurons as Alzheimer disease (AD) progresses, localizing to dystrophic neurites, which are known to correlate well with memory loss. Unlike trans p-tau, the cis cannot promote microtubule assembly, and is more resistant to dephosphorylation and degradation and more prone to aggregation. Pin1 accelerates cis to trans isomerization to prevent tau pathology in AD. Thus, during MCI and AD development, cis pThr231-Pro tau is the earliest detectable pathogenic tau conformation and antibodies and vaccines against the pathogenic cis p-tau may be used for the early diagnosis and treatment of AD. These findings offer in vivo approach to study conformational regulation of Pro-directed phosphorylation signaling.
Authors:
Kazuhiro Nakamura; Xiao Zhen Zhou; Kun Ping Lu
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2012-11-15
Journal Detail:
Title:  Prion     Volume:  7     ISSN:  1933-690X     ISO Abbreviation:  Prion     Publication Date:    2013 Mar-Apr
Date Detail:
Created Date:  2013-03-08     Completed Date:  2013-12-30     Revised Date:  2014-03-07    
Medline Journal Info:
Nlm Unique ID:  101472305     Medline TA:  Prion     Country:  United States    
Other Details:
Languages:  eng     Pagination:  117-20     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Alzheimer Disease / diagnosis,  metabolism*
Biological Markers / analysis,  metabolism
Humans
Immunoassay / methods*
Models, Molecular
Phosphoproteins / analysis,  metabolism*
Phosphorylation
Protein Conformation
Stereoisomerism
tau Proteins / analysis,  metabolism*
Grant Support
ID/Acronym/Agency:
R01 AG039405/AG/NIA NIH HHS; R01AG039405/AG/NIA NIH HHS; R01AG17870/AG/NIA NIH HHS; R01CA122434/CA/NCI NIH HHS; R01CA167677/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Biological Markers; 0/Phosphoproteins; 0/tau Proteins
Comments/Corrections

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