The Actin Cytoskeleton as a Novel Pathway in ALS Pathogenesis

The actin cytoskeleton is essential for structural support, movement, and communication with other cells. A lot of cellular energy is dedicated to maintaining actin networks. Even a slight impairment of actin with negligent short-term effects could, over time, provide an accumulative stress that eventually leads to a massive system failure. Many of the genes associated with ALS interact in some way with the regulation of actin and mutations in these genes can significantly alter the architecture and dynamics of the actin cytoskeleton. This indicates that dysregulation of actin may represent an undiscovered pathway motor neuron toxicity and cell death in ALS. However, the relationship between actin and ALS has not been extensively studied. In this project we will determine the role of the actin cytoskeleton in ALS disease progression caused by mutations in the ALS-associated genes PFN1 and SOD1. We will use an interdisciplinary approach that combines biochemistry, cell biology, imaging, and neuroscience. By studying the effect of these mutations on the actin cytoskeleton from single-molecule interactions to mouse models of the disease, we hope to uncover novel insights about how they cause dyshomeostasis and progressive cytotoxicity in motor neurons that leads to ALS.