The human HSP70/HSP40 chaperone family: a study on its capacity to combat proteotoxic stress

All cells are constantly threatened by both physical and chemical stress factors that can damage e.g. the DNA and proteins. Whereas the molecular mechanisms responsible for DNA repair have been studied in great detail, the mechanism underlying the repair and disposal of damaged proteins are far less investigated and less understood. It is well known that DNA damage in combination with a malfunctioning repair mechanism may ultimately lead to diseases such as cancer. But also damaged proteins and impaired protein repair are implicated in disease, in particular neurodegenerative diseases such as Huntingtons disease, various types of Spinocerebellar ataxias, Parkinsons disease and Alzheimers disease. All these diseases share a relative late age of onset and are currently incurable. To combat protein damage, cells contain large families of proteins, named chaperones, which assist in protein folding and repair. So far, only a minority of these proteins have been studied and the largest chaperone family in humans consists of the HSP70/HSP40 family. In this thesis, the results of the first elaborate and detailed study on the human HSP70/HSP40 family is presented. The characteristics of the family are systematically analyzed and compared using both bioinformatics as well as cell biological approaches. The functional chaperone activity is measured in various cellular models for neurodegenerative diseases. Our results show that a number of HSP40 chaperone proteins show a highly promising activity to suppress various progressive characteristics typical for neurodegenerative diseases.