PAR-1 for the course of neurodegeneration.
Cell. 2004 Mar 5;116(5):631-2.
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This paper describes an intriguing Drosophila model of tau phosphorylation causing tau neurotoxicity. So far, therapeutic approaches to tau pathology in AD did not progress beyond the preclinical stage and were mainly directed at the inhibition of the CDK5 and GSK3 kinases. However, the MARK pathway may offer more promising targets. We and others have recently shown that MARKs are activated by LKB1/Par-4 [1,2]. This may represent a neurotoxic signal which is not specific for AD pathology, since it was just shown that both LKB1 and MARK4 become rapidly upregulated in a murine stroke model .
Since confirmation of the Drosophila model by mouse knockouts may be difficult due to the presence of four MARK genes—whereas flies possess only a single gene—we may need to await the development of specific MARK inhibitors, and see whether these are able to inhibit P-tau (and Aβ-?) induced neuronal cell death.
This excellent paper draws renewed attention to the (other) central problem in neurodegeneration in general and AD in particular: How does the tau pathology originate? This essentially boils down to the question of what is the initial kinase, i.e., the kinase that triggers the phosphorylation that eventually results in hyperphosphorylation of tau and instigates the deadly cascade ending in paired helical filaments, neurofibrillary tangles and cell death. In that respect, tau is definitely the prime suspect and candidate "executer" of neurons in many neurodegenerative disorders, including AD. The pathological definition of AD as "plaques + tangles" does not allow or permit the AD field to escape this problem, despite the fact that amyloid attracts 10 times (my wild guess) more attention than tau.
Through the work of the Mandelkow lab and many others, the functions of MARK kinase have been defined in some detail, in terms of phosphorylating tau and other MAPs, and in terms of neurite outgrowth and polarization. What was missing was a definite link to pathology, and that is provided by this paper. The authors define PAR1 kinase as responsible for phosphorylation of serines 262 and 356 in tau, thereby causing cells to die. Many studies have indirectly implicated MARK, GSK-3, PKA, and CaMKII in phosphorylating these sites, but no animal study is yet available to validate these kinases as the physiological kinase for these sites.
So, are "S262 and S356" going to be magical for tau pathology as "β and γ" are for amyloid pathology? At the least, these serine residues are located in the region of tau that matters most, i.e., the microtubule-binding domain, which, incidentally, is also the region that is littered with mutations giving rise to the family of tauopathies known as FTD, or frontotemporal dementia! Antibody 12E8 specifically detects pS262 and pS356 in the MTBD of tau (Seubert et al., 1995), and it is definitely going to be popular and in demand among tauists and perhaps baptists. As always, many questions and some caveats remain. For one, the authors use not wild-type human tau, but the FTD mutant tau-R406W. This might explain why the final outcome is cell death but no tau aggregates in whatever form. Moreover, the choice of this mutant might have been fortuitous, since it is the most C-terminal of all known clinical mutations, closely positioned to the AD2/PHF1 epitope that is important in binding to MT and in tau aggregation (Spittaels et al., 2000; Vandebroek et al., 2004). Further along the path to understand it all remains the question why no mice have yet been produced (or reported) with overexpression or deficiency of MARK? Those who have such mice available should come forward and inform the community what and how and where …