. Alzheimer disease-specific conformation of hyperphosphorylated paired helical filament-Tau is polyubiquitinated through Lys-48, Lys-11, and Lys-6 ubiquitin conjugation. J Biol Chem. 2006 Apr 21;281(16):10825-38. PubMed.


Please login to recommend the paper.


  1. This is a well-performed study that mapped phosphorylation sites and polyubiquitination sites of paired helical fragment (PHF)-tau that was affinity-purified from the heat-treated soluble fraction of AD brain using monoclonal antibody MC-1. The authors confirmed many phosphorylation sites of PHF-tau reported by previous studies. They also identified five additional potential phosphorylation sites (i.e., Ser68, Thr71, Thr111, Ser113, and Thr414) in addition to the previously reported 37 sites on serine and threonine residues (see Gong et al., 2006, for the list of phosphorylation sites of PHF-tau). This study also supports a new hypothesis that abnormal hyperphosphorylation of tau is an early event that may be the key to the initiation of neurodegeneration (Alonso and Iqbal 2005; Gong et al 2006).

    Because polyubiquitin is found attached to the soluble PHF-tau, Cripps et al. proposed that polyubiquitination might also be an early modification event. However, abnormal hyperphosphorylation of tau had been observed in AD brain before polymerization into PHF, and this pool of hyperphosphorylated tau is not modified by ubiquitin (Bancher et al., 1991; Kopke et al., 1993). It is also possible that the soluble PHF-tau used in Cripps’s study might be derived from fragmented PHFs/NFTs (neurofibrillary tangles) that actually represent the late stage of tau pathology. In any case, we have shown that abnormal hyperphosphorylation is more likely to occur before being modified by polyubiquitination (Gong et al., 2005).


    . Tau-induced neurodegeneration: a clue to its mechanism. J Alzheimers Dis. 2005 Dec;8(3):223-6. PubMed.

    . Abnormal phosphorylation of tau precedes ubiquitination in neurofibrillary pathology of Alzheimer disease. Brain Res. 1991 Jan 18;539(1):11-8. PubMed.

    . Post-translational modifications of tau protein in Alzheimer's disease. J Neural Transm. 2005 Jun;112(6):813-38. PubMed.

    . Impaired brain glucose metabolism leads to Alzheimer neurofibrillary degeneration through a decrease in tau O-GlcNAcylation. J Alzheimers Dis. 2006 Mar;9(1):1-12. PubMed.

    . Microtubule-associated protein tau. Abnormal phosphorylation of a non-paired helical filament pool in Alzheimer disease. J Biol Chem. 1993 Nov 15;268(32):24374-84. PubMed.

Make a Comment

To make a comment you must login or register.