PhD position (Ageing & Disease; RNA Biology): Finding a therapy for Huntington’s Disease (m/f/d)PhD - Individual Supervisor

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" and "RNA Biology", the research group of Susann Schweiger offers the following PhD project:

Huntington’s Disease (HD) is a devastating neurodegenerative disorder that is caused by the expansion of a CAG repeat in the open reading frame of the Huntingtin gene, which is translated into an expanded glutamine stretch in the Huntingtin protein. It is inherited in an autosomal dominant way with a 50 % risk for children of patients to also develop the disease. A reduction of aberrant Huntingtin protein in a mouse model for HD has been shown to significantly improve the symptoms of the disease. Based on this we are looking into the possibility to reduce the load of aberrant Huntingtin protein and use this as a causative therapy in patients.

PhD Project: Phase separation and mTOR inhibition in Huntington’s Disease- development of a therapy

In previous work we have found that through a hairpin structure that is formed by the CAG repeats in the Huntingtin RNA a protein complex binds to the RNA that stimulates the translation of the Huntingin RNA. The longer the CAG repeat is, the more of this protein complex binds to the RNA and the stronger protein translation is stimulated. We could demonstrate that in cells carrying an expanded CAG repeat in the Huntingtin gene due to this mechanism significantly more Huntingtin protein is synthesized than in wildtype cells (Krauss et al., 2013).

We could further show that the RNP (ribo-nucleo-protein complex) described above carries the translation regulator mTOR (mammalian target of rapamycin) kinase. By inhibiting this kinase either with the specific inhibitor rapamycin or indirectly with metformin, the synthesis of disease causing Huntingtin protein is inhibited. Associated with this, symptoms of early phase HD were fully rescued in a mouse model of HD (Arnoux et al., 2018). Metformin has been used for Type II Diabetes for decades and has a very confined spectrum of side effects, which makes it a promising candidate for a therapy in HD patients.

The aim of this phD project is to further establish the mTOR containing RNP as a therapeutic target for HD. Within a collaborative research community (SFB 1551) in Mainz that connects polymer scientists with molecular biologists we will go a novel way into therapy development. We will characterize protein and RNA complexes and will study their involvement in liquid and solid cellular condensates, first in-vitro and then in-vivo in patients’ cells. We will study the role of metformin in these processes and will extend this and try to understand if interference with condensation of cellular molecules can be used as an efficient therapy for HD and other neurodegenerative disorders. We will closely collaborate with a group from the Max-Planck Institute for Polymer-Sciences that will focus on a computational effort to develop statistical mechanical models that mimic the ability of biomolecules to interact with their environment via non-specific interactions, as well as specific binding motifs, which will closely accompany and support the work on the bench.

We will use cellular as well as animal models for HD in this project. The work will be complemented by a clinical trial using Metformin  in patients in the clinical unit of the Institute of Human Genetics.

If you are interested in this project, please select Susann Schweiger as your group preference in the IPP application platform.

Qualification profile:

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:

• Master or equivalent
• Interactive personality & good command of English
• 2 letters of reference

We offer

·       Exciting, interdisciplinary projects in a lively international environment, with English as our working language

·       Advanced training in scientific techniques and professional skills

·       Access to our state-of-the-art Core Facilities and their technical expertise

·       Fully funded positions with financing until the completion of your thesis

·       A lively community ofmore than 190 PhD students from 44 different countries

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 19 April 2023. Interviews will take place at IMB in Mainz on 19-21 June 2023.

Starting date: 1 August 2023 – 1 February 2024