The upregulated presence of hyperphosphorated tau and absence of NFT-like structures in mutant tau X CHIP-knockout mice seem to indicate that hyperphosphorylation of tau is unlikely to be a major cause of aggregation. The proposal that polyubiquitination of tau may facilitate filament formation is interesting but does not seem to be consistent with human pathology in which tau ubiquitination takes place in the later stages of PHF formation.

View all comments by Takaomi Saido

This paper by Dickey et al. is a strong addition to mounting evidence that phosphorylated tau is a dangerous moiety. One way the neuron protects itself from this danger is to call upon CHIP, Hsc70, and ubiquitin to modify tau in a manner that may simultaneously promote tau aggregation. This body of data raises the question of why the cell then fails to degrade the aggregate in the proteasome. The usual response to this question invokes proteasomal overload, a reasonable idea other than the fact that no data is yet available to support or refute this hypothesis. However, in the face of proteasomal failure, a back-up strategy may be to move these non-degradable proteins into an inert aggregate.

Certainly, the cell harbors such a dangerous moiety as phosphorylated tau because it very likely serves an important function. Again data is scant, but the general notion of plasticity has been raised as a function for tau phosphorylation, specifically as an exquisitely precise regulator of tau binding to microtubules. Thus, phosphorylated tau is a double-edged sword with the potential...  Read more

This paper by Dickey et al. is a strong addition to mounting evidence that phosphorylated tau is a dangerous moiety. One way the neuron protects itself from this danger is to call upon CHIP, Hsc70, and ubiquitin to modify tau in a manner that may simultaneously promote tau aggregation. This body of data raises the question of why the cell then fails to degrade the aggregate in the proteasome. The usual response to this question invokes proteasomal overload, a reasonable idea other than the fact that no data is yet available to support or refute this hypothesis. However, in the face of proteasomal failure, a back-up strategy may be to move these non-degradable proteins into an inert aggregate.

Certainly, the cell harbors such a dangerous moiety as phosphorylated tau because it very likely serves an important function. Again data is scant, but the general notion of plasticity has been raised as a function for tau phosphorylation, specifically as an exquisitely precise regulator of tau binding to microtubules. Thus, phosphorylated tau is a double-edged sword with the potential to harm the cell while at the same time serving an important function. The validity of phosphorylated tau and the kinases which induce its phosphorylation as drug targets continue to rise, however, with the caveat that we are tampering with a tau phosphorylation state whose function is unknown.

View all comments by Kenneth Kosik