PROJECT SUMMARY Mechanotransduction is the ability of a cell to detect and respond to mechanical stimuli. This tightly regulated process allows cells to adapt to environmental and structural changes. The nucleus is a central regulator of mechanotransduction. As the nucleus detects a change of force, it responds by altering cell behavior and function. While extensive research in non-neuronal cell types has investigated mechanotransduction in the context of cell proliferation, metastasis, and differentiation within physiological and pathological conditions, few studies have investigated the role of mechanotransduction in neurons. The brain is exposed to changes in mechanical force from the vasculature, direct force impacts with the skull, and neurodegeneration. Tauopathies, including Alzheimer’s disease, are neurodegenerative disorders that involve the progressive deposition of tau protein in the brain. Mechanistically, pathogenic forms of tau have been found to drive neurodegeneration by inducing over-stabilization of the actin cytoskeleton, which causes destabilization of the lamin nucleoskeleton. Nucleoskeletal destabilization drives heterochromatin decondensation, aberrant gene expression, and ultimately neuronal death. I recently reported that neurons harboring pathological tau have a decrease in nuclear tension and a disruption in the Linker of Nucleoskeleton to Cytoskeleton (LINC) complex, an established nuclear mechanosensor. My preliminary studies indicate that neurons harboring pathological tau have a significant increase of emerin, a mechanosensitive protein that resides on the inner nuclear membrane and binds to A-type lamins. Studies in non-neuronal cells suggest that mechanical stimulation causes emerin to become phosphorylated and translocate to the cytoplasm, where it regulates actin dynamics. As neurons predominantly express B-type lamins, it is currently unknown if and how emerin regulates nuclear mechanotransduction in neurons. The overall goal of this proposal is to better understand mechanisms underlying nuclear mechanotransduction in neurons in physiological and pathological conditions. I will test the hypotheses that emerin is mechanosensitive in neurons and interacts directly with B-type lamins, and that pathogenic forms of tau disrupt nuclear mechanotransduction. Understanding how neurons detect and respond to mechanical forces will be instrumental to our understanding of basic neurobiology and disease.