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Disruptions in Protein Metabolism Cause Aging-Associated Diseases

Proteins play a life-sustaining role in the cell – how does it work?
Proteins are essential components of every cell. Protein quality control, the repair of defective and removal of irreparably damaged proteins, is of key importance for maintaining cell function. In human cells, this is accomplished by a range of quality control mechanisms. Special molecules, so-called chaperones, help newly synthesised proteins fold into the right three-dimensional structure. If a protein misfolds despite the presence of a chaperone and therefore cannot function properly, the ubiquitin/proteasome system breaks it down into amino acids, which are then recycled. This quality control no longer functions properly with increasing age. Improperly folded proteins can be neither repaired nor removed. The proteins clump and lead to a series of serious illnesses like Alzheimer’s, Parkinson’s and muscle disorders, but also to organ degeneration.

New insights into the interplay between protein metabolism, aging and lifespan
Using the C. elegans threadworm, CECAD scientists investigate which aging processes are influenced by the disposal and recycling of defective proteins. They have successfully identified components of the ubiquitin/proteasome system that are fundamentally responsible for regulating muscle development. Muscles are comprised of thick and thin protein strands, the myofibrils. These have to be carefully assembled by a complex protein machinery to ensure that the muscle functions under stress. Enzymes regulate this process, and stamp the muscle regulators with an expiration date. In threadworms scientists have successfully manipulated this expiration date, thus keeping damaged muscles active longer. The proper regulation of this system is a prerequisite for developing and maintaining muscle activity. Dysregulation leads to an aggregation of muscle proteins in the human body. They result in inflammation and muscle weakness that can ultimately lead to death. This discovery could be revolutionary for the therapy and diagnosis of some muscle disorders.

An additional question researchers from Research Area B are looking into is how protein quality control is regulated in individual cells and in united cell structures. They are trying to identify how the control mechanisms can be maintained in response to environmental and physiological challenges. In order to understand specific signalling pathways and reactions in the described proteostasis networks, CECAD scientists are analysing these processes in the tissue of different model organisms.

Prof. Dr. Thomas Benzing
Head of Research Area B – Principal Investigator, Kidney Research Center Cologne (KRCC)
Tel.  +49 221 478 4480
thomas.benzing[at]uk-koeln.de

Nephrologisches Forschungslabor
Uniklinik Köln
Kerpener Str. 62
50937 Köln
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Thomas Benzing

Prof. Dr. Thorsten Hoppe
Head of Research Area B – Principal Investigator, CECAD Cologne and Institute for Genetics
Tel.  +49 221 478 842 18
thorsten.hoppe[at]uni-koeln.de

Institut für Genetik
Universität zu Köln
Joseph-Stelzmann-Str. 26
50931 Köln
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Thorsten Hoppe
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Figures
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Figure 1: CECAD scientists take advantage of genetic model organisms. Here, the transparent soil nematode Caenorhabditis elegans is used to investigate PQC path-ways in vivo.

Figure 2: C. elegans mutants shown in this picture are defective in protein degradation pathways in the intestine, which often cause premature aging phenotypes. The defects are visualized by green fluorescence of a stabilized model substrate.

Figure 3 and 4: C. elegans embryos undergo cycles of rapid cell division, which allows following the distribution of labeled proteins by time-lapse microscopy. Here, a DNA replication factor is localized inside the nucleus during S-phase of the cell cycle. Defects in this process result in genomic instability.

Figure 5: Myotubes derived from myoblasts of myopathy patients or control cells.

Figure 6: are stained for different muscle specific differentiation marker proteins to monitor disease related developmental and structural defects.