Microtubule-affinity regulating kinase

NFTs are comprised of paired helical filaments that aggregate in dense bundles. Paired helical filaments are formed from tan protein. Tan protein provides structural support to microtubules, the cell s transportation and skeletal support system. When tan filaments undergo abnormal phosphorylation at a specific site, they cannot bind effectively to microtubules, and the microtubules collapse. Without an intact system of microtubules, the cell cannot function properly and eventually dies. Overactivity of kinases such as microtubule affinity-regulating kinase, or underactivity of phosphatases could theoretically produce or prevent breakdown of abnormally phosphory-lated tan protein. NFTs are found in other dementing illnesses besides AD, and may represent a common method by which various inciting factors culminate in cell death. ... 

Schaar BT, Kinoshita K, Mcconnell SK (2004) Doublecordn microtubule affinity is regulated by a balance of kinase and phosphatase acdvity at die leading edge of migradng neurons. Neuron 41 203— 213. 

Among the structural proteins which are subject to GSK-3 regulation, the microtubule-associated protein tau is a prime target in Alzheimer s disease pathology. Tau binds to tubulin and promotes microtubule assembly and stability in a phosphorylation-dependent manner. The phosphorylation status of tau is balanced by antagonistic kinase and phosphate activities. Inappropriate hyperphosphorylation of tau is a key event in contributing to cytoskeletal abnormalities and tau pathology in Alzheimer s disease. When hyperphos-phorylated, tau s affinity for the microtubule is reduced and as a consequence tau dissociates from the microtubules. This leads to abnormal accumulation... 

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