Thinking of doing your PhD in the Life Sciences? The International PhD Programme (IPP) on Gene Regulation, Epigenetics & Genome Stability is offering talented, young scientists the chance to work on cutting edge research projects. As an IPP PhD student, you will join a community of exceptional scientists working on diverse topics ranging from how organisms age or how our DNA is repaired, to how epigenetics regulates cellular identity or neural memory.
Activities and responsibilities:
In the fields of “Ageing & Disease”, the IPP research group of Prof. Dorothee Dormann offers the following PhD project:
Role of disease-linked phosphorylation in TDP-43 proteinopathies
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are progressive age-related neurodegenerative diseases for which currently no therapies are available. A molecular hallmark of both disorders is mislocalization and cytosolic aggregation of the RNA-binding proteins TDP-43 (TAR DNA binding protein of 43 kDa) or FUS (Fused in sarcoma). The molecular mechanisms leading to RNA-binding protein pathology in these disorders and how it could potentially be prevented or reversed is currently not well understood.
Recently, we found that nuclear import receptors (importins) and post-translational modifications (e.g. arginine methylation or phosphorylation) can protect against aberrant phase separation and aggregation of disease-linked RNA-binding proteins. We aim to better understand these quality control mechanisms, their general relevance for aggregation-prone proteins, under what conditions they operate in cells, how their failure contributes to ageing or disease and whether we can harness them in new therapeutic approaches.
Abnormal post-translational modifications (PTMs) have been identified in several neurodegenerative diseases, e.g. FUS is hypomethylated in FTD patients, and TDP-43 is hyperphosphorylated and polyubiquitinated in ALS and FTD. Aberrant PTMs could play an important pathological role in neurodegeneration and contribute to protein mislocalization, aggregation and/or functional impairment, eventually leading to neuronal dysfunction. Alternatively, disease-linked PTMs may have a protective role and counteract these pathological changes. We have recently shown that C-terminal hyperphosphorylation of TDP-43, which occurs in ALS and FTD patients, might be such a protective mechanism, as it suppresses aberrant phase separation and solidification of TDP-43. In this project, we will explore under which cellular conditions phosphorylation arises on TDP-43, which kinases are relevant for C-terminal TDP-43 hyperphosphorylation and how it affects the cellular behavior of TDP-43, e.g. its protein-protein-interactions, turnover or modification with other PTMs. The project will involve the screening of kinase inhibitor or CRISPR libraries to identify relevant kinases and proteomics to identify protein-protein interactions or map PTM sites. Candidates with a strong background in cell biology or biochemistry are encouraged to apply
What we offer:
Are you an ambitious, young scientist looking to push the boundaries of research while interacting with colleagues from multiple disciplines and cultures? Then joining the IPP is your opportunity to give your scientific career a flying start!
All you need is:
For more details on the projects offered and how to apply via our online form, please visit www.imb.de/phd.
The deadline for applications is 3 May 2021. Interviews will take place online 5 – 9 July 2021.
Starting date: 1 September 2021 – 1 March 2022