Finding a therapy for Huntington’s Disease
1 PhD project offered in the IPP summer call 2023
Scientific Background
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.
Publications relevant to this project
Michels S, Buchholz HG, Rosar F, Heinrich I, Hoffmann MA, Schweiger S, Tüscher O, Schreckenberger M. (2019) 18F-FDG PET/CT: an unexpected case of Huntington's disease. BMC Neurol. May 1;19(1):78. Link
Arnoux I#, Willam M#, Griesche N#, Krummeich J, Watari H, Offermann N, Weber S, Narayan Dey P, Chen C, Monteiro O, Buettner S, Meyer K, Bano D, Radyushkin K, Langston R, Lambert JJ, Wanker E, Methner A, Krauss S*, Schweiger S*, Stroh A*. (2018) Metformin reverses early cortical network dysfunction and behavior changes in Huntington's disease. Elife. Sep 4;7. pii: e38744. Link
Krauß S, Griesche N, Jastrzebska E, ChenC, RutschowD, AchmüllerC, DornS, BoeschSM, LalowskiM, WankerE, SchneiderR, SchweigerS.Translation of HTT mRNA with expanded CAG repeats is regulated by the MID1-PP2A protein complex (2013). Nature communications, 4:1511 Link