A new screening assay reveals that aminoglycoside antibiotics interfere with the Tau/MDM2 interaction

Abstract

MAPT gene mutations cause some neurodegenerative tauopathies and the MAPT-encoded protein Tau is deposited in neurofibrillary tangles, hallmarks of this disease family. In addition to its canonical function in regulating microtubule dynamics, Tau modulates chromatin compaction, gene expression, and the cellular response to DNA damage. During the DNA damage response, Tau positively modulates P53 by binding to MDM2 thereby preventing P53 inactivation and degradation. The aberrant presence of both MDM2 associated to neurofibrillary tangles and of P53 misfolding in brains affected by neurodegenerative diseases suggests that the sequestration of MDM2 may prevent P53 clearance in tauopathies and so contribute to progressive neuronal dysfunction and death. Following this evidence, a pharmacological inhibition of the Tau/MDM2 interaction may represent a viable strategy to reduce P53-dependent cell damage in brain disorders. With the screening FDA-approved drugs and natural compounds, we discovered that members of the aminoglycoside antibiotic family antagonize the Tau/MDM2 interaction. The use of these reagents may advance the understanding of the implication of the Tau/MDM2/P53 axis in neurodegeneration models. However, their unfavorable pharmacokinetic properties may limit their systemic use when targeting the brain.