Unraveling Anti-IgLON5 disease-associatedtauopathy with neuroproteomics.

Overview

Project Summary

This collaborative project aims to uncover the initial changes in intracellular signaling and proteostasis that lead to neurofibrillary tangle (NFT) formation and neurodegeneration in a non-genetic rodent tauopathy model of anti-IgLON5 disease. Anti-IgLON5 disease is a recently described autoimmune neurological disorder in which patients present with abnormalities of sleep, movement, cognition, and accumulation of NFTs. Autoantibodies to the uncharacterized neuronal cell adhesion protein IgLON5 (anti-IgLON5 IgGs) are thought to cause anti-IgLON5 disease, but the underlying molecular mechanism is unknown.

We will combine our complementary expertise in cell adhesion proteins, and proteomics and neurodegeneration. We will elucidate the IgLON5 interactome and gain new insights into the pathological mechanism of anti-IgLON5 IgGs to determine how patient derived anti-IgLON5 IgGs alter the brain proteome and phosphoproteome. In contrast to classical genetic models of tauopathy, which do not replicate disease contributing factors such as neuroinflammation and NFT diversity, our model will allow the elucidation of the precise timeline and sequence of molecular events underlying the pathological onset of tauopathy.

Ultimately, we will provide new insights into the general molecular mechanisms underlying neurodegeneration in tauopathies and gain specific insight into the pathogenesis of anti-IgLON5 disease, for which there is currently no treatment. Since anti-IgLON5 disease patients generate high levels of anti-IgLON5 IgGs, which are likely to induce IgLON5 loss of function along with a decline in sleep and cognition, this project will also lay the groundwork for understanding the role of IgLON5 in these critically important processes.

Project Details