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Akt and CHIPcoregulate taudegradation throughcoordinatedinteractions Chad A. DickeyJohn KorenYong‐Jie Zhang2008 год

Akt and CHIP coregulate tau degradation through coordinated interactions
статья из журнала

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Аннотация: A hallmark of the pathology of Alzheimer's disease is the accumulation of the microtubule-associated protein tau into fibrillar aggregates. Recent studies suggest that they accumulate because cytosolic chaperones fail to clear abnormally phosphorylated tau, preserving a pool of toxic tau intermediates within the neuron. We describe a mechanism for tau clearance involving a major cellular kinase, Akt. During stress, Akt is ubiquitinated and degraded by the tau ubiquitin ligase CHIP, and this largely depends on the Hsp90 complex. Akt also prevents CHIP-induced tau ubiquitination and its subsequent degradation, either by regulating the Hsp90/CHIP complex directly or by competing as a client protein with tau for binding. Akt levels tightly regulate the expression of CHIP, such that, as Akt levels are suppressed, CHIP levels also decrease, suggesting a potential stress response feedback mechanism between ligase and kinase activity. We also show that Akt and the microtubule affinity-regulating kinase 2 (PAR1/MARK2), a known tau kinase, interact directly. Akt enhances the activity of PAR1 to promote tau hyperphosphorylation at S262/S356, a tau species that is not recognized by the CHIP/Hsp90 complex. Moreover, Akt1 knockout mice have reduced levels of tau phosphorylated at PAR1/MARK2 consensus sites. Hence, Akt serves as a major regulator of tau biology by manipulating both tau kinases and protein quality control, providing a link to several common pathways that have demonstrated dysfunction in Alzheimer's disease.
Год издания: 2008
Авторы: Chad A. Dickey, John Koren, Yong‐Jie Zhang, Ya-Fei Xu, Umesh K. Jinwal, Morris J. Birnbaum, Bobby R. Monks, Mei Sun, Jin Cheng, Cam Patterson, Rachel M. Bailey, Judith Dunmore, Sareh Soresh, Carlos M.M.P. Leon, Dave Morgan, Leonard Petrucelli
Издательство: National Academy of Sciences
Источник: Proceedings of the National Academy of Sciences
Ключевые слова: Alzheimer's disease research and treatments, Cholinesterase and Neurodegenerative Diseases, Endoplasmic Reticulum Stress and Disease
Другие ссылки: Proceedings of the National Academy of Sciences (HTML)
Europe PMC (PubMed Central) (PDF)
Europe PMC (PubMed Central) (HTML)
Carolina Digital Repository (University of North Carolina at Chapel Hill) (HTML)
PubMed Central (HTML)
PubMed (HTML)