Regulation of protein degradation and homeostasis by ubiquitylation

The majority of cellular functions are performed by proteins, making it vital to a cell to maintain functional proteins and destroy damaged ones, a process known as proteostasis. There is a progressive decline in proteostasis during the ageing process that results in the accumulation of damaged proteins. Loss of proteostasis and accumulation of misfolded and aggregated proteins is a common contributing factor to age-related diseases such as Alzheimer’s disease, Huntington’s disease, Parkinson’s disease and Amyotrophic Lateral Sclerosis (ALS). Damaged proteins need to be tagged with a destruction signal called ubiquitin. The ubiquitin signals are recognized by the proteasome, a large molecular machine which unfolds and degrades the damaged proteins. Ubiquitin signals are removed by a family of enzymes called deubuiquitinating enzymes (DUBs) and in line with this important regulatory function, mutated DUBs are implicated in several human diseases. The main goals of our research are to understand how ubiquitin signals target proteins for degradation, and how protein degradation is regulated by DUBs. I anticipate that our research will provide important insights into how proteostasis is regulated. An improved understanding of this fundamental process will form the basis for the development of novel strategies to combat neurodegenerative disorders