Protein folding is one of the fundamental processes in life, and therefore needs to be tightly regulated. Many cellular protein quality control (PQC) systems are in place to ensure that protein homeostasis (proteostasis) is optimally adjusted for a changing environment, facilitating protein biogenesis, folding, translocation and degradation. Among these systems are the molecular chaperones and the major protein degradation machineries, namely the ubiquitin proteasome system and autophagy. However, as a result of ageing, mutations or exogenous influences, the capacity of the PQC systems can be exhausted and protein misfolding and aggregation, including the formation of amyloids, can occur. There are many known diseases in which protein misfolding and aggregation is the underlying cause of the pathological conditions; these are referred to as proteinopathies and include neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease and Huntington’s disease. Scientists in the group of Heidi Olzscha aim to understand the underlying mechanisms of PQC systems, in particular Ubiquitin-like domain (UBL) containing proteins and find approaches to prevent cytotoxicity due to protein misfolding. Over the last decade, it has become clear that posttranslational modifications (PTMs) can govern and modulate protein folding, and that aberrant PTMs can cause or contribute to proteinopathies. The scientists also study the influence of PTMs, especially ubiquitination, acetylation and citrullination, and how they affect the PQC systems as well as the turnover and interactors of proteins prone to misfolding.
Protein quality control
In order to ensure the correct protein folding and protection of the proteome, eukaryotic cells developed a complex protein quality control (PQC) system. Molecular chaperones, the ubiquitin proteasome system (UPS) and autophagy form a network, which maintains the integrity of the proteome. The group of Heidi Olzscha analyses the interplay between different parts of the PQC, with a focus on Ubiquitin-like domain (UBL) containing proteins. We collaborate with the group of Dr. Ori (Leibnitz Institute on Aging, Jena, Germany) to quantitate the changes of interactors upon PQC disturbance with biological chemistry approaches. By using CRISPR/Cas9 technology, we can determine the influence of these proteins on the PQC systems.
Proteinopathies or protein misfolding diseases are a descriptive term for illnesses caused by protein misfolding. They encompass not only the ageing-related neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease or Huntington’s disease, but also systemic diseases. It is still unclear which factors can modulate the diseases and lead to an early onset. Our group analyses degradation-pathways of different aggregating proteins and tests compounds and proteins to find out how degradation of these proteins can be facilitated.
In a collaborative project with Prof. Rujescu and Dr. Jung (Martin Luther University Halle-Wittenberg, Germany), we analyse the route of aggregating proteins through the blood-brain barrier (BBB) and how their appearance and aggregation status is altered upon the crossing of the BBB. We study this in a patient-derived iPS model with biochemical and cell biological methods.
Posttranslational modifications (PTMs)
Ubiquitination is a reversible PTM which occurs at lysine residues of proteins and can target proteins for degradation by the UPS. Acetylation is another PTMs at lysine residues and is therefore competing with ubiquitination. We use chemical biology approaches to study the consequences of shifting the equilibrium from ubiquitination to acetylation and how the flux through the proteasome is changing. For this purpose, we analyse components of the UPS and their interaction partners for altered acetylation pattern and how their degradation may be affected. This includes misfolding-prone proteins.
Citrullination is the conversion of the amino acid arginine in proteins into citrulline. As far as it is known, it is an irreversible process and can also lead to aberrant protein folding. This results in changing interaction profiles of these aberrantly folded proteins as well as recognition of the citrullinated proteins by autoantibodies. There is clear evidence that the citrullinated proteins play a central role in the pathogenesis of rheumatoid arthritis. In collaboration with the group of Prof. Midwood at the Kennedy Institute, University of Oxford, we aim to understand the influence of citrullination on selected proteins of the matrisome and potential changes in inflammatory signalling processes.
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We are grateful for funding from the following sources:
- Deutsche Forschungsgemeinschaft (DFG), GRK 2155 ProMoAge
- European Union, Social Funds, HalOx
- State Saxony-Anhalt, Wilhelm-Roux funds
- Since 2019: Project leader in the DFG-funded GRK 2155 ProMoAge.
- Since 2018: Principal investigator at the Institute of Physiological Chemistry, Medical Faculty, Martin Luther University Halle-Wittenberg.
- 2016 – 2018: Celgene Fellow, Department of Oncology, Medical Faculty, University of Oxford, United Kingdom.
- Since 2016: Associated Fellow of the Higher Education Academy (AFHEA), University of Oxford, United Kingdom.
- 2013 – 2016: Fulford Junior Research Fellow in Medicine, Somerville College, University of Oxford, United Kingdom.
- 2011 – 2013: EMBO long-term Fellow, Department of Oncology, Medical Faculty, University of Oxford, United Kingdom.
- 2005 – 2007: PhD Kekulé Fellow, Funds of the Chemical Industry, Germany.
- 2005 – 2010: Graduate studies at the Max Planck Institute of Biochemistry, PhD in Biochemistry from the Ludwig Maximilian University in Munich, Germany, about structural determinants underlying the cytotoxic effects of aggregating proteins.
- 1999 – 2004: Biochemistry and Molecular Biology, University of Hamburg, Diploma thesis in tumour biology at the Institute of Clinical Chemistry/Central Laboratory, Medical Faculty, University Hospital Hamburg-Eppendorf, Germany.