Project Summary/Abstract: Neurodegenerative diseases are among the fastest growing clinical burdens on society, and in the next 20 years Alzheimer’s Disease (AD) is projected to overtake cancer as the second leading cause of death in adults. Despite AD prevalence, there are currently no therapeutic interventions to combat the underlying pathology driving disease progression. While much is still not understood about neurodegenerative pathogenesis, the accumulation of extracellular amyloid- plaques and intracellular tau tangles are undisputed hallmarks of AD. To combat disease progression, an attractive therapeutic strategy is to investigate impairments in native proteostatic mechanisms used to dispose of this neurotoxic protein accumulation. One such mechanism which has been implicated in the development and progression of not only AD, but numerous neurodegenerative proteinopathy disorders including Parkinson’s and Huntington’s disease, is the autophagy-lysosomal network (ALN). The ALN is a bulk degradative system utilizing vesicular transport to dispose of large protein aggregates which contribute to neuronal dysfunction. This process relies on the active remodeling of the actin cytoskeleton to initiate, capture, and transport neurotoxic cargo for degradation and maintain proper proteostasis. However, mechanistically how dysregulations in cytoskeletal dynamics are associated with neurodegenerative pathology contributing to disease remains unclear. Through multiple behavioral neurodegenerative screens, we have identified an actin depolymerizing factor, cofilin, along with its upstream molecular regulators, which upon modulation improve neurodegenerative behavioral deficits and lower tau accumulation in vivo. This proposal seeks to investigate how cytoskeletal dynamics contribute to AD through genetic attenuation of the cofilin-centric cytoskeletal remodeling pathway. I hypothesize that modulating the activity of cofilin and its regulators will ameliorate AD neurodegenerative phenotypes via modification of the cytoskeleton and proteostasis. Aim 1 will utilize behavioral and histological approaches to investigate how genetic modulation of numerous genes within the remodeling pathway influence neurodegenerative phenotypes in tauopathy Drosophila and mouse models. In Aim 2, I will investigate mechanistically how this cytoskeletal remodeling pathway is involved in the formation and progression of the ALN through 1) measuring changes in neurotoxic protein accumulation upon cytoskeletal genetic modulation using various tauopathy model systems, and 2) utilizing high resolution microscopy techniques in AD patient derived induced pluripotent stem cells (iPSCs) along with biochemical in vitro assays, to investigate how genetically modulating cofilin disrupts various phases of the ALN. Upon successful completion of this project, we will identify molecular impairments of cytoskeletal remodeling associated with neurodegeneration that are involved in proteostat...