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Jinwal, Umesh K.

A5112774582 | I4210140006

Mayo Clinic

USF Health Byrd Alzheimer's Institute

Citations 5

O4‐04‐08: Neuronal tau‐specific stress induction of molecular chaperones: The failure of a coping mechanism

Alzheimer's & Dementia | August 1, 2011 | Volume: 7 | Issue: 4S_Part_20 | Pages: No page available

10.1016/j.jalz.2011.05.1996

The Diarylheptanoid (+)-aR,11S-Myricanol and Two Flavones from Bayberry (Myrica cerifera) Destabilize the Microtubule-Associated Protein Tau

Journal of Natural Products | December 8, 2010 | Volume: 74 | Issue: 1 | Pages: 38-44

10.1021/np100572z | PMID 21141876

P3‐425: Chaperone‐mediated modulation of tau aggregation correlates with modifications in tau pathology and synaptic plasticity

Alzheimer's & Dementia | July 11, 2010 | Volume: 6 | Issue: 4S_Part_19 | Pages: No page available

10.1016/j.jalz.2010.05.1968

O1‐06–03: Akt functions to regulate the chaperone complex and attenuate Tau degradation

Alzheimer's & Dementia | July 24, 2008 | Volume: 4 | Issue: 4S_Part_4 | Pages: No page available

10.1016/j.jalz.2008.05.258

Akt and CHIP coregulate tau degradation through coordinated interactions

Proceedings of the National Academy of Sciences | February 21, 2008 | Volume: 105 | Issue: 9 | Pages: 3622-3627

10.1073/pnas.0709180105 | PMID 18292230

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.