The physiology and pathophysiology of unfolded protein responses.

Cells choke on their own misfolded proteins when internal quality-control systems fail. This project investigates how two different cellular compartments—the endoplasmic reticulum and the mitochondria—detect and signal that protein-folding crisis, and whether those signals can be deliberately tweaked. The problem is that chronic protein misfolding underpins many age-related diseases, including neurodegeneration and metabolic disorders. Current understanding of the signalling pathways is incomplete, especially for the mitochondrial unfolded protein response, which remains poorly mapped. Without that molecular detail, designing drugs to correct or compensate for the stress response is guesswork. The researchers will focus on three levers inside the endoplasmic reticulum: the phosphorylation switch on a key translation factor, the hyperoxidising enzyme ERO1, and the metabolic links that connect ER stress to whole-body ageing. For mitochondria, they will use genetic screens to identify the signalling components that trigger when proteins fail to fold inside that organelle. This is fundamental science. If it succeeds, it will provide a molecular wiring diagram of stress signalling that pharmaceutical developers could eventually use to design compounds that boost secretion of mutant proteins or protect cells from stress-induced death. No immediate clinical application is promised, but the pathways under study are the same ones that go awry in diabetes, Parkinson’s disease, and other conditions of ageing.