Many neurodegenerative diseases involve the accumulation of misfolded proteins as part of the process of disease progression. Alzheimer’s disease “plaques” are the best-known example of this phenomenon, but many different proteins have been identified in many different diseases, suggesting that malfunctions in how proteins are made, or recycled, in the brains of patients is a fundamental aspect of neurodegenerative disease.
This project uses a “mouse model” of neurodegeneration where the ability of cells to breakdown and recycle old proteins is impaired. This leads to progressive development of neurodegeneration over the course of a few weeks, providing more evidence that protein recycling is a key contributor to disease mechanisms. Using this model, the project is investigating the step-by-step changes in brain signalling pathways that develop due to impaired protein recycling. We are using a combination of molecular proteomics (analysing individual proteins), network analysis (investigating how those proteins interact) and anatomical labelling, to investigate how the initial “trigger” of protein misfolding can lead to neuronal death.
We have found that a specific transcription factor known as STAT3 is upregulated very early in the process of degeneration and appears to regulate the development of an inflammatory response known as reactive gliosis that precedes the onset of neuronal death. Understanding the molecular basis of this early signalling process will hopefully improve our knowledge of how neurodegenerative diseases develop and worsen.
I am extremely thankful to the NSG@QMC for their generous funding of this PhD.