Institute for Genetics, Faculty of Math. Nat. Sciences
Prof. Dr. Thorsten Hoppe
Principal Investigator, Institute for Genetics
The ubiquitin/proteasome system (UPS) is a major proteolytic route functioning in a cellular network to maintain the proteome during stress and aging. Another proteolytic system supporting proteostasis is the autophagy-lysosome pathway that degrades proteins inside activated autophagosomes. Age-related impairment of either of these systems causes enhanced protein aggregation and affects lifespan, suggesting functional overlap and cooperation between the UPS and autophagy in stress and aging. The ultimate goal of Prof. Dr. Thorsten Hoppe and his team is to assemble a global picture of the stress-induced proteolytic networks critical for aging and age-related diseases.
Our research: Prof. Thorsten Hoppe and his team are using the nematode Caenorhabditis elegans to study physiological aspects of selective protein turnover in the context of aging-associated processes, such as muscle development and regeneration, protein aggregation, and genome stability. They take advantage of fluorescent reporter proteins that allow them to evaluate the activity of both 26S proteasome and autophagy in transgenic worms. This approach has already been used for genetic screening, which provides insight into the regulation of the proteolytic machinery. Initial results indicate that the dynamics of different proteolytic pathways are controlled by stress-induced signaling mechanisms. Identifying the critical regulators would help to characterize the underlying principles. In addition to intracellular proteostasis networks, Hoppe and his team’s long-term mission is to understand non-cell-autonomous regulation of protein degradation through paracrine factors. Intercellular communication via stress signals may coordinate cells of different tissues and counteract the aging process of the organism as a whole. The team’s goal is to understand the crosstalk between stress-induced proteolytic pathways and the aging of multicellular organisms.
Our successes: Prof. Hoppe’s research group has identified regulatory mechanisms that coordinate protein degradation systems and the aging process. Defects in proteolysis often result in the accumulation and aggregation of misfolded proteins in the human brain, causing motor and speech deficits. By manipulating the degradation machinery, Prof. Hoppe and his team were able to delay the aging process and extend the lifespan in C. elegans. These findings may be relevant for future therapeutic interventions against degenerative aging-associated diseases, such as Alzheimer’s, Huntington’s, and Parkinson’s disease.
In addition, Prof. Hoppe’s studies have identified mechanisms that are involved in inclusion body myopathy. Based on his results, it is possible to prevent the premature loss of central muscle proteins and therefore extend muscle activity. Since muscles lose both structure and stability with age, this topic is highly relevant to current aging research.
Our goals: The scientists aim to understand the role of key proteolytic pathways in triggering aging-associated diseases. Besides intracellular proteostasis networks, the working group’s long-term goal is to investigate non-cell-autonomous regulation. The intercellular transduction of stress signals may coordinate cells of different tissues and the aging process of multicellular organisms.
Our methods/techniques: The research group combines studies in C. elegans and primary cell cultures from patients with various diseases. The activity of the proteasome and autophagy is usually monitored by fluorescent marker proteins in transgenic worms. Genome-wide sequencing approaches are used in C. elegans to explore the transcriptional regulation of different proteolytic systems.
Figure 1: Expression of green fluorescent protein (GFP)-based substrates allows rapid quantification of protein turnover in different tissues of C. elegans. The right panel shows a mutant worm with proteolytic defects and substrate stabilization.
Figure 2: Disease related mutations known to cause huntington‘s disease challenge tissue specific proteostasis networks. In contrast to wild-type (left), polyglutamine containing proteins form protein aggregates in muscle cells of mutant worms.
Figure 3: C. elegans embryos depleted for CDC-48UFD-1/NPL-4 stained with anti-Tubulin (red) and anti-CDT-1 antibodies (green).
Figure 4: C. elegans body-wall muscle cells (actin in red) with protein aggregates/inclusion bodies (green).
Cell nuclei are stained with DAPI (blue).
Figure 5: We take advantage of the powerful genetic model Caenorhabditis elegans, which allows addressing tissue-specific differences in aging relevant proteostasis pathways.