Actin filaments (F-actin) and microtubules (MTs) are highly charged rod-like polyelectrolytes formed by polymerization of G-actin and tubulin subunits, respectively. These cytoskeleton filaments are essential for directional growth, shape, division and other important biological activities in eukaryotic cellular processes. Mutations in G-actin / tubulin genes are often evident in pathological conditions. Actin mutations may cause dilated or hypertrophic cardiomyopathies, congenital skeletal myopathies and deafness. Whereas tubulin mutations are associated with fetal malformations of cortical development. When subjected to intracellular biological environment alterations, even normal G-actin and tubulin genes are associated with dysfunctions and malformations in F-actins / Mts such as dysregulated assembly, misleading protein binding, abnormal polymerization stability, and defective electric signal transmission. The basis for cytoskeleton filaments to transmit electric signals and overcome electrostatic interactions to form bundles and networks appears primarily dominated by the polyelectrolyte nature of these filaments rather than their tertiary structures. However, the underlying biophysical principles and molecular mechanisms that support the polyelectrolyte nature of F-actin and MTs, and their properties are still poorly understood due to the lack of appropriate methodologies. In this research project an innovative approach for cytoskeleton filaments is proposed to balance accurate and efficient computational tools with experimental techniques, making it possible for the first time, to comprehensively and efficiently characterize bundling formation and electric signal propagation under the numerous intracellular environments and filament molecular structures that are usually present in normal and pathological conditions. It is hypothesized that molecular and/or cellular alterations, often evident in pathological conditions caused by age and inheritance, break down equilibrium and competition between the molecular mechanisms that dominate the bundling and conducting properties of cytoskeleton filaments in normal conditions. The overall goal of this research proposal is to determine the impact of excessive alterations in the intracellular environment and variations in the filament charge produced by isoforms and mutations on the polyelectrolyte properties of cytoskeleton filaments. The outcomes of this proposal is expected to provide an unprecedented molecular understanding on why and how age and inheritance conditions induce dysfunctions and malformation in cytoskeleton filaments. This understanding may advance the prevention and/or treatment of a variety of diseases. It may also open unexplored frontiers in neuroscience. It might elucidate whether cytoskeleton filaments and axon membranes are able to transmit different kind of information and what might be the role of electrical signal propagation along filaments in neuronal cable-like theories.
Substantial evidence on bundling formation and electric signaling propagation supports the polyelectrolyte nature of actin filaments and microtubules, however the biophysical principles underlying these phenomena still remain elusive. This understanding is crucial to advance the development of new treatments for a variety of muscular, degenerative, and deafness diseases which are associated with dysfunctions and malformation of these cytoskeleton filaments.
