The role of PHR signaling in tauopathy-related neurodegeneration

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.

Grant Number: 1R15NS137207-01
NIH Institute/Center: NIH
Principal Investigator: Melissa Borgen