Molecular reporters for measuring proteostasis capacity in cell

Protein homeostasis (proteostasis) describes the maintenance of the proteome in a proper folded state by an extensive quality control network. Under normal proteostasis conditions, protein synthesis, proper folding and localisation, as well as the timely degradation and disassembly of abundant proteins are in balance. Perturbation of proteostasis often leads to the accumulation of misfolded proteins and aggregates, which has been linked to many neurodegenerative diseases such as Alzheimer’s, Parkinson’s and Huntington’s Diseases. Pharmacologic manipulation of the proteostasis network to improve its capacity is emerging as a new therapeutic strategy for these conditions.

Given the importance of proteostasis in protein folding in cells and their association with diseases, we are interested to develop chemical tools to quantitatively measure the proteostasis capacity at the population and individual cell level. We have recently developed a general-purpose probe scheme based on a unique small molecule fluorogen (fluorescence turn-on sensor) to measure the unfolded protein load, which reflects on the proteome stress, in cells. In this project, a series of new probes are synthesized and will be used in combination with other techniques to study how the proteome unfolds under stress conditions and how the key quality control system deals with the unfolded proteins in these conditions.