Unravelling the mechanism of transcellular chaperone signalling in C. elegans

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Age-related diseases including Alzheimer's, Parkinson's and Huntington's Disease is one of the biggest challenges for our aging society. The onset of these devastating diseases share a common feature, where unhealthy cells in the brain accumulate deformed proteins so-called misfolded proteins. To repair these proteins and restore health, cells have evolved a protective mechanism called stress responses where a family of proteins called chaperones will be produced to fix the damaged proteins. My research using the round worm nematode C. elegans has demonstrated a novel inter-tissue communication that allows a stressed organ to send out an alert to healthy cells in other organs to instruct them producing more protective chaperones. This process is called transcellular chaperone signalling (TCS) and is also found in mammals. Currently, the key question for TCS and its mechanisms relevant to human diseases is to search for the "messenger" that regulates this inter-tissue communication. Our preliminary observation showed that PQM-1 (a protein factor that controls gene expression) and ASP-12 (a putative secretory molecule) both play a key role in TCS and stress response. We are planning to understand how they function in these events and their roles in the onset of human diseases. Using C. elegans, we will build a new tool that will reveal the protective role of core chaperones in stress response across all tissues in the worms. We will monitor the chaperone expression during normal developmental processes, stress response and TCS to comprehensively understand how "transcellular chaperone expression" could be developed as a novel therapeutic approach to treat protein misfolding diseases. In other words, this means that we could activate protective chaperones from a healthy tissue which then "signals" to a tissue affected by disease (e.g. brain) to produce more protective chaperone. Our work will generate invaluable information that can be indicative to researchers using rodent models to study stress responses in an intact animal. Our approach will provide a great alternative tool to perform pilot studies in C. elegans prior the mammalian animal experiments. This approach will greatly reduce the amount of animals used in these kinds of experiments.Our aim is to understand how cells cope with stress and how tissues communicate with each other to perform stress response. The innovative research conducted in our team will push the boundary to search for potential treatments for human diseases caused by the accumulation of mis-folded proteins.