Lay summary

Ribonucleic acid (RNA) plays a central role in the expression of genetic information both as an information carrier (messenger RNA [mRNA]) and as a regulator (micro-RNA [miRNA]). Reflecting its important role for life, uncontrolled alterations of RNA metabolism often leads to disease. For example, research during the last years revealed that mutations in proteins with roles in RNA metabolism are implicated in a wide variety of neurodegenerative diseases, but the pathogenic mechanisms leading to these disorders are not yet understood. This research project focuses on the RNA-binding protein FUS (fused in sarcoma, also known as translated in liposarcoma, TLS) and aims at elucidating its biological function(s).  Mutations in the FUS gene have recently been identified in patients with an inherited form of amyotrophic lateral sclerosis (ALS). Most of these mutations lead to cytoplasmic accumulation of FUS aggregates in neurons and glial cells of these ALS patients. Moreover, such FUS aggregates are also the characteristic hallmark lesions in a subset of patients with frontotemporal lobar degeneration (FTLD).

FUS is a ubiquitously expressed protein with several structural motifs in the C-terminal half that appear to be involved in nucleic acid binding. Consistent with this, FUS has been implicated in a variety of cellular processes linked to RNA metabolism, miRNA maturation, and DNA repair, but its exact function is not yet clear. With an interdisciplinary team of experts in both RNA biology and molecular pathology of neurodegenerative disorders, and with a broad spectrum of methods, comprising structural biology, biochemistry, molecular and cell biology, and transgenic mouse models, we plan to i) identify genome-wide the RNAs and proteins interacting with FUS, ii) determine the structural basis for the specificity of these interactions, iii) understand the molecular role of FUS in selective miRNA maturation, regulation of alternative splicing, and DNA damage response, and iv) find out how a failure in any of these potential functions of FUS can lead to neurodegeneration and specifically to death of motor neurons.

The results of this project are expected to not only reveal the molecular mechanism leading to FUS-associated ALS and FTLD, but generally to provide significant new insight into the emerging connection between misregulation of RNA metabolism and neurodegeneration, a connection that is currently implied in a variety of additional neurological diseases. Understanding these molecular mechanisms will serve as the basis for future development of effective therapies.