The material properties of the cytosol control the biochemistry of the cell and influence all molecular interactions by regulating rates of intracellular diffusive transport. Despite this critical role, these properties remain poorly understood, and it is unclear to what extent the cytosol is homogeneous, whether there are differences between cell types, and if these properties are stable or dynamic. It has recently been discovered that yeast cells regulate their cytosolic properties in response to stress, namely glucose-starvation and aging. These stresses result in a decrease in cell volume and an increase in cytosolic crowding, inducing widespread phase separations and aggregation of polyglutamine (polyQ)-proteins. This type of polyQ-protein aggregation is the molecular hallmark of neurodegenerative diseases like Huntington's Disease (HD), and is very poorly understood. In this project, I will produce the first description of the biophysical properties of the neuronal cytosol, and I will directly test whether aged or nutrient-deprived neurons, or neurons from an HD mouse model exhibit changes in these properties. I propose that viscosity and density of mammalian cells, and in particular neuronal cells, are dynamic properties that can be actively regulated in response to environmental changes. In particular, I will test two hypotheses: - H1: Nutrient starvation and aging induce changes to the material properties of the neuronal cytosol. - H2: A neuronal stress-response upon starvation or aging is sufficient to trigger aggregation of polyQ-proteins. Combining state-of-the-art techniques and expertise in the fields of neurobiology, metabolism, and biophysics, my investigation of these novel and potentially paradigm shifting hypotheses could fundamentally alter our understanding of the material properties of the neuronal cytosol, and ultimately reveal new therapeutic strategies for the most common inherited neurodegenerative disorders.
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