Tau phosphorylation at Alzheimer's disease-related Ser356 contributes to tau stabilization when PAR-1/MARK activity is elevated

Abstract

Abnormal phosphorylation of the microtubule-associated protein tau is observed in many neurodegenerative diseases, including Alzheimer’s disease (AD). AD-related phosphorylation of two tau residues, Ser262 and Ser356, by PAR-1/MARK stabilizes tau in the initial phase of mismetabolism, leading to subsequent phosphorylation events, accumulation, and toxicity. However, the relative contribution of phosphorylation at each of these sites to tau stabilization has not yet been elucidated. In a Drosophila model of human tau toxicity, we found that tau was phosphorylated at Ser262, but not at Ser356, and that blocking Ser262 phosphorylation decreased total tau levels. By contrast, when PAR-1 was co-overexpressed with tau, tau was hyperphosphorylated at both Ser262 and Ser356. Under these conditions, the protein levels of tau were significantly elevated, and prevention of tau phosphorylation at both residues was necessary to completely suppress this elevation. These results suggest that tau phosphorylation at Ser262 plays the predominant role in tau stabilization when PAR-1/MARK activity is normal, whereas Ser356 phosphorylation begins to contribute to this process when PAR-1/MARK activity is abnormally elevated, as in diseased brains.

Ca2+/calmodulin-dependent protein kinase II promotes neurodegeneration caused by tau phosphorylated at Ser262/356 in a transgenic Drosophila model of tauopathy

“…UAS-CaMKII (32) and UASala (33) are gifts from Dr. Leslie Griffith (Brandeis University). The transgenic fly line carrying UAS-S2Atau was reported previously (10,11,34). All experiments were performed using female flies at 35 day-old after eclosion unless otherwise indicated.…”

Structural basis of the interplay between α-synuclein and Tau in regulating pathological amyloid aggregation

“…Tau is a microtubule-binding protein, and six isoforms, owing to alternative splicing, are found in the brain (26). Hyperphosphorylation of Tau leads to its detachment from microtubules, resulting in its mislocalization and ultimate pathological aggregation in the brains of patients with AD and other tauopathies (27)(28)(29). Four microtubule-binding repeat domains (R1-R4) were shown to mediate Tau fibril formation (30).…”

Mechanism involved in insulin resistance via accumulation of β-amyloid and neurofibrillary tangles: link between type 2 diabetes and Alzheimer’s disease

“…Various experimental paradigms suggest that Aβ and tau have been found to exert synergistic modes of toxicity, while the effect of insulin on the brain is complex and not confined to Aβ production ( Figure 5 ). 2 , 9 , 18 , 113 , 114 Tau protein plays a wider role in cellular shape, motility, and signal transduction in AD. The C-terminal of this protein is probably responsible for tubulin-binding and the acidic N-terminal region interacts with other cytoskeletal elements.…”