Regulated intracellular protein degradation to counter disease

Hovedområde:Protein chemistry
Målgruppe:Biochemistry, Molecular Biomedicine, Biology
Niveau:Bachelor, Masters

As a result of cellular stress, genomic mutations or defects in protein synthesis, cells produce misfolded proteins. Since such misfolded proteins are prone to form highly toxic intracellular aggregates, our cells have evolved various “quality control” measures to cope with the presence of such partially denatured proteins. The two main alleviatory strategies employed are either to shield the misfolded proteins from aggregation and refold them to the native state by molecular chaperones, or, if the native state is unachievable, to target the proteins for degradation via the ubiquitin-proteasome system. Faults in either of these systems lead to accumulation of toxic protein species which in turn may trigger diseases, including several neurodegenerative disorders. In our studies of the cellular stress response to protein misfolding, we utilize human tissue culture cells and the fission yeast Schizosaccharomyces pombe as model organisms. As the molecular chaperones and ubiquitin-proteasome system are remarkably well conserved we tend to use yeast for answering basic cell biological questions as this allows for swifter molecular biological manipulations without limiting the overall scope of the projects. However, when yeast cannot be utilized we use human cells in tissue culture. Primarily our approach to gaining insight into the molecular mechanisms of intracellular protein degradation is focused on identifying and characterizing novel components of the system. To this end we utilize a variety of genetic, biochemical and molecular biological techniques including co-immunoprecipitation, yeast two-hybrid analyses, cDNA suppressor screens and high throughput siRNA screening. These studies are then typically followed up by generation of mutants and various cell biological techniques, such as pulse-chase experiments and following protein aggregate formation by fluorescence microscopy. Various projects related to degradation of misfolded proteins are available at the Bachelor’s, Master’s or Ph.D. level. For more specific detail, contact Rasmus Hartmann-Petersen for an informal meeting.

Anvendte metoder:Protein chemistry, Cell biology, Molecular Biology, Genetics
Keywords:ubiquitin, proteasome, chaperone, stress, disease
Vejleder(e): Rasmus Hartmann-Petersen