Stress Response Networks in Organismal Proteostasis

Project Summary

The goal of the project is to elucidate the molecular mechanisms by which protective stress responses prevent the toxicity of aggregation-prone beta amyloid (Aβ) protein. Alzheimer's disease patients are featured with aggregation of abnormally folded beta amyloid proteins in the brain that interfere with the cellular functions of neurons and eventually lead to their degeneration. It has been suggested that stress response factors may protect against the proteotoxicity associated with Alzheimer's disease. However the molecular mechanisms are still poorly understood.

We hypothesize that different stress response pathways are integrated in a coordinated network and enable the protection against Aβ proteotoxicity that occurs both in the Aβ expressed tissue and the neighboring tissues. Here we set out to use the C. elegans models of Alzheimer's disease to characterize the protective stress response network, focusing on how neurons sense the toxic Aβ aggregation and how they communicate with neighboring tissues to achieve an organismal protection.

The first aim of the study is to identify the molecular functions of evolutionarily conserved transcription factors involved in responses to different cellular stresses, such as heat stress, oxidative stress and unfolded protein stress in the context of Aβ proteotoxicity. We will examine both the Aβ expressed neurons and the neighboring tissues to dissect the cell autonomous and non-autonomous responses. We expect Aβ toxicity does not only trigger stress responses in neurons, but also causes imbalance of protein homeostasis, and thus induces stress responses in neighboring tissues as well. On the other hand, the responses in distal tissues may provide positive feedback and enhance the protective stress responses in neurons. This trans-cellular signaling could provide a way of integrating different stress response pathways that have tissue specificity and end up with robust organismal protection. The second aim of the study is to examine the impact of aging and chronic proteotoxicity on stress responses. To test the hypotheses that aging and/or chronic proteotoxicity impair the protective responses, we will characterize the integrated stress response network in neurons and neighboring tissues in animals of different ages and with different lengths of exposure to Aβ aggregates. These studies will elucidate the interactions of aging, stress response, and gain-of-function impacts of Aβ aggregation, and also shed light on the potentials for re-engineering the stress response pathways for extended protection during aging.