E3 ligases and FKBP14 are potential drug targets for AD therapy. Increasing the activity of non-canonical E3 ligases by drugs or gene therapy could prevent Tau aggregation. CHIP has been suggested to target phosphorylated Tau for ubiquitination and subsequent degradation; therefore, CHIP is hypothesized to be a canonical E3 ligase for phosphorylated Tau. We postulate that in the AD brain, CHIP is impaired or overloaded, which causes a failure to maintain Tau turnover. In the occipital lobe, a region less impacted by AD, TRIM32/37 act as compensatory E3 ligases and help to maintain Tau protein turnover. As previously described, FKBP14 catalyzes Tau aggregation. FK506 (an FKBP inhibitor) has been reported to have neuroprotective effects; however, it also acts as an immunosuppressant. Novel drug therapies for AD should also focus on a non-immunosuppressive FKBP inhibitor that can cross the blood-brain barrier or a compound that can activate E3 ligases.
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]