Human Cathepsin F: An unusual cysteine protease involved in neurodegeneration

Lysosomal cysteine cathepsins play key roles in various physiological and pathological processes, including aging, neurodegeneration and genetic diseases. Their disregulated activities result in numerous human diseases and consequently are promising drug targets. Among eleven human cysteine cathepsins, cathepsin F is one of the less studied and characterized proteases. The recent discovery of several mutations within the human cathepsin F gene was a significant breakthrough that has provided strong evidence that this enzyme is associated with Type B Kufs disease, an adult onset neuronal ceroid lipofuscinosis (CLN13), and other neurodegenerative disorders. The major focus of this research will be to study the effects of cathepsin F mutations on enzyme activity, processing of cathepsin F proenzyme and the biological role of its proregion containing a cystatin-like domain. In addition we will determine the structures of procathepsin F and mature cathepsin F in complex with its inhibitor(s) and specific substrates. The results will provide insight into the cathepsin F functional network at the molecular level, which serves as a general model system for NCLs and other neurodegenerative diseases. Our integrative approach will map out the topological and dynamic properties of the underlying biological networks. The project combines various fields of expertise such as biochemistry including proteomics, molecular and cell biology, X-ray crystallography and bioinformatics. The results of these studies will not only impact basic science but also provide important information contributing to the development of treatment strategies for Type B Kufs disease and other neurodegenerative diseases.