November 23, 2022

Monitoring Protein-RNA Interaction Signatures for Neurodegenerative and Myodegenerative Diseases by Mass Spectrometry

1st Call, Tech Trans

Short Summary

Protein-RNA interactions regulate important biological processes and are involved in many diseases, including neuro- and myodegenerative diseases. In this collaborative project, we will develop signatures for such (dys)functional interactions and use them to monitor regulatory processes in disease models and actual patient tissues. The approach will generate new insights into perturbed protein-RNA interactions in disease and should guide the development of new therapeutic strategies.

Goals

In this project, we will use a technology – developed jointly by the participating groups at ETH – that provides unique insight into the molecular organization of protein-RNA complexes. The method is based on cross-linking with ultraviolet light to stabilize interactions between protein and RNA. We will then use a technique called mass spectrometry to identify interacting regions. The approach, termed CLIR-MS, has already provided valuable insights for other protein-RNA complexes. In this Technology Translation project, we will extend the application of the method to samples of clinical relevance (cell lines, brain and muscle tissue), to derive a new kind of interaction marker that takes the structural and functional context into account.

Significance

Neurodegenerative and myodegenerative diseases remain very challenging targets for treatment. As just one example, ALS is a multifactorial disease with sporadic and hereditary forms, and various proteins have found to play key roles. The outcome of this project will help to better understand the relevance of RNA-binding proteins in such diseases, providing the basis for improved diagnostic and therapeutic avenues. More specifically, the project will serve as a pilot study for using cross-linking data as a basis for interaction markers in disease-related applications. In this regard, the concept can be extended to other diseases involving protein-RNA interactions and is scalable to larger sample numbers.

Background

RNA-binding proteins are known to play a role in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) as well as the myodegenerative disease, inclusion body myopathy (IBM). For example, the protein TDP-43 has been implicated in all three diseases, but the exact role of this and other proteins in disease onset and progress remains to be elucidated in detail. A better understanding of the underlying mechanisms will be possible by studying protein-RNA interactions at the molecular level.