Effect of tetracycline family of antibiotics on actin aggregation, resulting in the formation of Hirano bodies responsible for neuropathological disorders

Abstract

Actin, an ATPase superfamily protein, regulates some vital biological functions like cell locomotion, cytokinesis, synaptic plasticity and cell signaling in higher eukaryotes, and is dependent on the dynamics of actin polymerization process. Impaired regulation of actin polymerization has been implicated in the formation and deposition of rod-like paracrystalline structures called as Hirano bodies in neuronal cells of patients suffering from Alzheimer’s disease, Pick’s disease, Guam amyotrophic lateral sclerosis and parkinsonism–dementia complex. Aggregation of actin forming amorphous deposition in the brain cells is also associated with chronic alcoholism and aging of the neurons. In the current article, we propose the breaking of the highly amorphous and dysregulated actin aggregates using generic compounds like tetracycline, oxytetracycline, doxycycline and minocycline which are used as antibiotics against tuberculosis and infection caused due to various Gram-negative bacteria. We have investigated the effect and affinity of binding of these four compounds to that of actin aggregates using 90° light scattering, size exclusion chromatography, dynamic light scattering, circular dichroism, scanning electron microscopy, transmission electron microscopy imaging and kinetic analysis. The isothermal calorimetric measurements showed that the binding constant for the cycline family molecules used in this study range from 9.8 E4 M−1 to 1.3 E4 M−1. To understand the in vivo effect, we also studied the effect of these drugs on Saccharomyces cerevisiae Δend3 mutant cells. Our data suggest that these generic compounds can plausibly be used for the treatment of various neurodegenerative diseases occurring due to Hirano body formation in brain cells.Communicated by Ramaswamy H. Sarma