The laboratory of Dorothee Dormann focuses on the molecular mechanisms of neurodegenerative diseases, most notably FTD (frontotemporal dementia) and ALS (amyotrophic lateral sclerosis). FTD and ALS are currently incurable, with patients usually dying within a few years of disease onset. Existing therapies are designed to treat only the symptoms of disease and no therapies are available to slow down or stop disease progression. The main objective of our research is to obtain a molecular understanding of the mechanisms underlying FTD and ALS in order to develop new therapeutic approaches.
Scientific Background
Post translational modifications (PTMs) play an important role in modifying protein function and cell physiology, but have also been linked to many diseases, including neurodegenerative disorders. Several proteins that form insoluble aggregates in neurodegeneration patients, e.g., Tau in Alzheimer’s disease and the RNA-binding proteins TDP-43 or FUS in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), are abnormally post-translationally modified. Aberrant PTMs could play an important pathological role in neurodegeneration and contribute to protein mislocalisation, aggregation and/or functional impairment. Alternatively, PTMs may have a protective role and counteract these pathological changes. So far, even though several different PTMs have been detected on TDP-43 and FUS in different proteomic studies, it is largely unclear which PTMs are specific to physiological or pathological conditions, and how these PTMs alter the proteins’ polymer and phase separation behaviour as well as their functional properties in cells.
The Project
A variety of different PTMs (e.g. phosphorylation, methylation, acetylation, ubiquitylation and SUMOylation) have been identified on TDP-43 and FUS either in low throughput and proteomic studies (www.phosphosite.org), however this data is a collection from diverse cell and tissue types under different conditions. It is therefore not known which of these PTMs occur under basal conditions and which arise under stress or disease conditions. Moreover, the functional impact of the diverse PTMs of TDP-43 and FUS is largely unclear. In this project, we plan to systematically identify PTMs on TDP-43 and FUS in neuron-like cells exposed to different stress conditions and in ALS/FTD post-mortem brains, using biochemical purifications and PTM proteomics. Moreover, we seek to investigate the functional impact of diverse PTMs on the proteins’ biophysical properties and phase separation/aggregation behavior, on their interactions with nucleic acids and RNA regulatory functions, as well as their subcellular localization and transport. To this end, the candidate will have the chance to develop and apply a variety of biophysical, biochemical and cellular techniques to study the functions of post-translational modifications on disease linked RNA-binding proteins.
Requirements of the candidate
• PhD in biochemistry, biology, biophysics or related discipline
• Extensive experience with mass spectrometry or biophysical characterization of IDPs
• Team player with enthusiasm to engage in collaborations and other lab projects
• Highly curious and open-minded, motivated to develop and drive an ambitious project
Publications Relevant to the Project
Sternburg EL, Gruijs da Silva LA, Dormann D. Post-translational modifications on RNA-binding proteins: accelerators, brakes, or passengers in neurodegeneration? Trends Biochem Sci. 2021 Aug 5:S0968-0004(21)00160-2.
Gruijs da Silva L, Simonetti F, Hutten S, Riemenschneider H, Sternburg EL, Pietrek LM, Gebel J, Doetsch V, Edbauer D, Hummer G, Stelzl LS, Dormann D. Disease-linked TDP-43 hyperphosphorylation suppresses TDP-43 condensation and aggregation; BioRxiv doi: https://doi.org/10.1101/2021.04.30.442163
Hofweber M, Dormann D. Friend or foe - post-translational modifications as regulators of phase separation and RNP granule dynamics, J. Biol. Chem, 2019 May 3;294(18):7137-7150
Hofweber M, Hutten S, Bourgeois B, Spreitzer E, Niedner-Boblenz A, Schifferer M, Ruepp MD, Simons M, Niessing D, Madl T, Dormann D. Phase separation of FUS is suppressed by its nuclear import receptor and arginine methylation. Cell 2018 Apr 19;173(3):706-719.e13
How to apply
Please see details on the project, information on how to apply, and an online application form at www.imb.de/postdocs. IMB is an equal opportunity employer.
Starting date: 1 April 2022 or later. The deadline for applications is 25 November 2021. Interviews will take place in Mainz on 20-21 January 2022
Application webpage: http://www.imb.de/postdocs
