Axonal beading, or the formation of a series of swellings along the axon, and retraction are commonly observed shape transformations that precede axonal atrophy in Alzheimer's disease, Parkinson's disease, and other neurodegenerative conditions. The mechanisms driving these morphological transformations are poorly understood. Here, we report controlled experiments that can induce either beading or retraction and follow the time evolution of these responses. By making quantitative analysis of the shape modes under different conditions, measurement of membrane tension, and using theoretical considerations, we argue that membrane tension is the main driving force that pushes cytosol out of the axon when microtubules are degraded, causing axonal thinning. Under pharmacological perturbation, atrophy is always retrograde, and this is set by a gradient in the microtubule stability. The nature of microtubule depolymerization dictates the type of shape transformation, vis-a `-vis beading or retraction. Elucidating the mechanisms of these shape transformations may facilitate development of strategies to prevent or arrest axonal atrophy due to neurodegenerative conditions.

Mechanical properties of cell membranes are known to be significantly influenced by the underlying cortical cytoskeleton. The technique of pulling membrane tethers from cells is one of the most effective ways of studying the membrane mechanics and the membrane-cortex interaction. In this article, we show that axon membranes make an interesting system to explore as they exhibit both free membrane-like behavior where the tether-membrane junction is movable on the surface of the axons (unlike many other cell membranes) as well as cell-like behavior where there are transient and spontaneous eruptions in the tether force that vanish when F-actin is depolymerized. We analyze the passive and spontaneous responses of axonal membrane tethers and propose theoretical models to explain the observed behavior.

Axonal beading-formation of a series of swellings along the axon-and retraction are commonly observed shape transformations that precede axonal atrophy in Alzheimer's, Parkinson, and other neurodegenerative conditions. The mechanisms driving these morphological transformations are poorly understood. Here we report controlled experiments which can induce either beading or retraction and follow the time evolution of these responses. By making quantitative analysis of the shape modes under different conditions, measurement of membrane tension, and using theoretical considerations, we argue that membrane tension is the main driving force that pushes cytosol out of the axon when microtubules are degraded, causing axonal thinning. Under pharmacological perturbation, atrophy is always retrograde and this is set by a gradient in the microtubule stability. The nature of microtubule depolymerization dictates the type of shape transformation vis à vis beading or retraction. Elucidating the mechanisms of these shape transformations will facilitate development of strategies to prevent or arrest axonal atrophy due to neurodegenerative conditions.

We present a multiscale modeling framework to predict the adhesion of a model particles from nano-to-micron scales of different shapes and compliances that mimic functionalized nanoparticles to biological cells by virtue of being decorated with receptors/antibodies in their surface. The model derives cell surface receptor interactions with functionalized peptides using atomistic simulations. These interaction potentials are then fit to predefined functions which are used to characterize the interaction between the particle/cells with substrates and to measure the free energy of adhesion/binding constants. Further, in this framework we also account for variations in the receptor ligand interactions due to the inherent compliance in the bilayer membranes on which the receptors are tethered. These calculations are performed using a standalone framework for estimating effect of membrane shape/curvature on the flexibility of the receptors. This membrane-compliance effect shows that decrease in membrane area results in increased receptor rigidity which ends up limiting the overall adhesion of the receptors to the functionalized surfaces or in other words much weaker dissociation constants (i.e. mM as opposed to microM). In this work we show a computational tool where we couple chemistry of peptide, membrane fluctuations and cellular sizes to estimate the overall binding affinities of these model cells to functionalized surfaces. We also showcase the power of this framework in simulating realistic heterogeneity in cell surface receptors by demonstrating effect of a combination of weak and strong receptors in modulating the overall binding affinity of the cell. The model as it stands can be a tool for development of functionalized surfaces aimed at cell based assays and or cell based therapies.