Project F
ON THE ROLE OF HEAT SHOCK PROTEINS PROTEIN FOLDING DISEASES AND AGEING
Prof. dr. Harm H. Kampinga
Department of Cell Biology, University Medical Center Groningen, Groningen, The Netherlands
In several types of tissue, but particularly in the brain, functional, differentiated cells do not divide and are required to last a lifetime. Aging in these types of cells appears to be partially influenced by the accumulation of damaged or incorrectly folded proteins. Incorrectly folded proteins run the risk to form aggregates that can lead to cellular dysfunction and eventually cell death. Such processes are enhanced in hereditary diseases such as Huntington's Disease neurodegenerative protein folding diseases). In these diseases, the cells produce large amounts of incorrectly folded proteins right from birth. Cells have protein quality control systems that are able to prevent or dispose of the unfolded or aggregated proteins; a main group of these so-called “chaperones” are Heat Shock Proteins (Hsp) and these play the central role in preventing irreversible protein aggregation. With age, the activity of these systems decreases while at the same time the number of damaged proteins actually increases. This is caused by an accumulation of DNA errors, errors in protein synthesis or by direct protein damage (oxidation, nitrosylation). Protein homeostasis and its disruption is therefore considered a crucial part of cellular aging.
Within the Department of Cell Biology, the function of the human chaperonome in relation to the aging process is being studied with the aim to find ways to stimulate specific parts of this system in order to inhibit the progression of protein folding diseases and to promote healthy aging
Chaperonome-wide screens are conducted in cell models to identify novel candidates within these large Hsp families with potential to combat the toxicity associated with several human protein folding diseases. Using molecular biology, biochemistry, and molecular imaging we try to elucidate mechanisms of action of individual the chaperones. Validation of in vivo effectivity as well as effects of the chaperones on longevity is performed using Drosophila melanogaster as a model system.
