paired helical filament (PHF)
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Structure
- pairs of approximately 10 nm filaments wound into helices with a periodicity of 160 nm visible on electron microscopy
- width varies between 10-22 nm
- the major component of PHF is a hyperphosphorylated form of microtubule-associated protein tau.*
- PHF are composed of disulfide-linked antiparallel hyperphosphorylated tau proteins
* a constitutively activated form of CDK5/p23-35 may hyperphosphorylate tau
* glycogen synthase kinase 3-beta (GSK3-beta) has also been implicated in hyperphosphorylation of tau
Pathology
- PHF are the major component of neuropil threads & neurofibrillary tangles of Alzheimer's disease (AD).
- PHF may also be seen in some but not all dystrophic neurites associated with neuritic plaques (amyloid plaques).
- PHF tau may be truncated of its C-terminal 20 amino acid residues.
- proteolysis by one of several caspases at Asp-421 is implicated.[7]
- dendrites & perikarya may contain PHF.[1]
- the mechanisms underlying PHF formation are uncertain but hyperphosphorylation of tau may disengage it from microtubules[5], increasing the soluble pool of tau
- certain types of phosphorylation of tau (by MAPK & GSK3, by MARK & PKA - at KXGS motifs within repeat region, especially Ser-262 & Ser-214) tend to inhibit PHF formation[6]
More general terms
Additional terms
- Alzheimer's disease (ADD)
- CDK5/p23-35 activator complex
- glycogen synthase kinase 3-beta (GSK3B)
- neurofibrillary tangle (NFT)
References
- ↑ 1.0 1.1 Gray et al Neuropathol Appl Neurobiol 13:91 1987 (in dendrites)
- ↑ Mori et al Science 235:1641 1987
- ↑ Selkoe DJ. Alzheimer's disease: genes, proteins, and therapy. Physiol Rev. 2001 Apr;81(2):741-66. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/11274343
- ↑ Maccioni et al The molecular bases of Alzheimer's disease and other neurodegenerative disorders. Archives of Medical Research 32:367, 2001 PMID: https://www.ncbi.nlm.nih.gov/pubmed/11578751
- ↑ 5.0 5.1 Lee VM et al, Neurodegenerative tauopathies Annu Rev Neurosci 24:1121-59, 2001 PMID: https://www.ncbi.nlm.nih.gov/pubmed/11520939
- ↑ 6.0 6.1 Friedhoff P, von Bergen M, Mandelkow EM, Mandelkow E. Structure of tau protein and assembly into paired helical filaments. Biochim Biophys Acta. 2000 Jul 26;1502(1):122-32. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/10899437
- ↑ Gamblin TC et al, Caspase cleavage of tau: linking amyloid and neurofibrillary tangles in Alzheimer's disease. Proc Natl Acad Sci U S A. Aug 19;100(17):10032-7. 2003 PMID: https://www.ncbi.nlm.nih.gov/pubmed/12888622
- ↑ Ksiezak-Reding H, Wall JS. Characterization of paired helical filaments by scanning transmission electron microscopy. Microsc Res Tech. 2005 Jul;67(3-4):126-40. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/16104001