Wang YP, Biernat J, Pickhardt M, Mandelkow E, Mandelkow EM. Stepwise proteolysis liberates tau fragments that nucleate the Alzheimer-like aggregation of full-length tau in a neuronal cell model. Proc Natl Acad Sci U S A. 2007 Jun 12;104(24):10252-7. PubMed.
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Boise State University
This eloquent study examines the post-translational modification of tau. The authors used a previously developed model of tauopathy by expressing the mutant tau repeat domain first discovered in FTP with PD linked to chromosome 17 (FTDP17). Several points of this study bear mentioning: first, the authors demonstrate that proteolytically cleaved fragments enhance the aggregation of full-length tau, a finding that has been previously reported following the caspase-cleavage of tau (1,2). Intriguing about this new study is that the identity of the proteases involved in cleaving tau is not known. Although tau is a well-known substrate for caspases and calpains, the role of other potential proteases has not been investigated. It will be interesting to follow whether the identity of these potential proteases will be revealed and what exactly is their role during the progression of AD.
Another interesting finding of this study is the demonstration that aggregation of tau is modulated by phosphorylation but does not depend on it. One dilemma in this area of AD is how these two events, proteolytic processing of tau and hyperphosphorylation, are related (see 3 for a recent review).
A question that remains to be fully answered is whether cleavage of tau precedes or follows phosphorylation. Several studies have suggested that the caspase cleavage of tau indeed precedes mature NFT formation (2,4) and is an early event associated with tangle pathology. In this manner, hyperphosphorylation may serve as a protective mechanism limiting the degree of aggregation of proteolytic fragments of tau together with full-length tau.
Another important finding of the present study is the revelation that cellular toxicity was dependent upon the aggregation of tau, but also upon the proteolytically derived fragments. This is an interesting and important observation, as several studies have suggested that C-terminally derived fragments of tau following caspase cleavage are themselves proapoptotic (5,6). The findings suggest that, depending on which protease cleaves tau, divergent pathways of toxicity may be invoked that either arise from the fragments themselves or follow aggregation. Overall, the present study has revealed important findings regarding the turnover of tau. Post-translational modification of tau appears to be a mechanism that may promote the pathology associated with AD.
References:
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Chung CW, Hong YM, Song S, Woo HN, Choi YH, Rohn T, Jung YK. Atypical role of proximal caspase-8 in truncated Tau-induced neurite regression and neuronal cell death. Neurobiol Dis. 2003 Dec;14(3):557-66. PubMed.
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