Project Summary Neurodegenerative diseases cause a progressive loss of neuronal function. Currently, an estimated 6 million Americans are live with dementia. Diagnosis often happens after symptoms start and irreversible damage has already occurred. Patients face a bleak prognosis, as treatments are ineffective at halting disease progression. Better treatments will rely on earlier diagnosis and drugs that stop progressive degeneration. To identify biomarkers and promising drug targets, we need to understand the cellular and molecular mechanisms underlying degenerative processes. Tau protein aggregation is a hallmark of several neurodegenerative diseases and is highly correlated with symptoms. Tau is known to bind and regulate microtubule stability. Several post-translational modifications of Tau have been documented, though the significance on symptom severity is unclear. It is critical that we identify the signaling downstream of Tau to find novel targets. To address our overall objective, we are using genetics to reveal a novel role for the highly conserved RPM-1 signaling network in degeneration in a C. elegans tauopathy model. RPM-1 is a key regulator of neural development, but recent work shows roles for RPM-1 orthologs in axon degeneration following injury. RPM-1 also promotes synapse maintenance and, importantly, was shown to be genetically inhibited by ptl-1/Tau during development. Our rationale is that genetic analysis will identify a new signaling network with Tau in neurodegeneration and how this network influences different stages of neurodegeneration. Completion of Aim 1 will reveal the Tau and RPM-1 genetic network in neurodegeneration. Aim 2 will yield a comprehensive time course analysis of synaptic, mitochondrial, and microtubule dynamics changes that occur from development through late stage degeneration. We will also assess how the network identified in Aim 1 affects these cellular changes at key time points. The innovation of this proposal is the novel Tau network that includes the RPM-1 pathway. Additionally, time-course analysis of subcellular changes will provide a timeline of key phenomena directly correlating with degeneration. We also will microtubule dynamics, which is not widely done and has never been done in vivo in a tauopathy model. This proposed research is significant because it will provide new insights into the genetic and molecular mechanisms underlying neurodegeneration, as well as potential targets for future drug development. Importantly, this proposal will satisfy key objective of the R15 mechanism by 1) significantly enhancing exposure of students to molecular biology research and 2) strengthening the research infrastructure at the Florida Institute of Technology.