The proposed AD model that involves Tau phosphorylation, prion-like misfolded protein propagation, and the deregulation of UPS, HSP90, and FKBP co-chaperones

Fig. 6_Heese

The proposed AD model that involves Tau phosphorylation, prion-like misfolded protein propagation, and the deregulation of UPS, HSP90, and FKBP co-chaperones. In AD, various physiological conditions are altered, including kinase over-expression or Aβ-induction increases in cellular kinase activities. As a result, the phosphorylation-prone Tau protein becomes hyperphosphorylated and loses its ability to bind with microtubules. It is subsequently misfolded and acts as a seed for prion-like transmission to adjacent neurons where it aggregates into NFTs. In AD brains, the UPS system is impaired as a result of inhibition by Aβ or aberrant gene expression, which is possibly triggered by an aberrant AICD signaling cascade. TRIM32/37, important E3-ligases, are down-regulated, which impairs the protein degradation pathway. In addition, the down-regulation of HSP90 might also impair hyperphosphorylated Tau clearance. HSP90 and CHIP target hyperphosphorylated Tau for proteasomal degradation. The FKBP14 co-chaperone, which is up-regulated in AD brains, prevents Tau degradation by binding to Tau and increasing its stability via interaction with the PPIase domain. Detached Tau loses its function and impairs the axonal transport pivotal for neuron survival. In this paradigm, Tau is involved in both the loss-of-function of axonal transport and gain-of-toxicity via prion-like transmission; in addition, impaired UPS and HSP90 function and FKBP14 overexpression promote pathophysiological conditions.

Reference:

The Ubiquitin-Proteasome System and Molecular Chaperone Deregulation in Alzheimer’s Disease.
Sulistio YA, Heese K.
Mol Neurobiol. 2015 Jan 7. [Epub ahead of print]

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