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Emmy Noether Junior Research Group - RNA-binding proteins in neurodegenerative diseases: Transport processes and pathomechanisms

  • Project Leader: Dr. Dorothee Dormann
  • Affiliation: Biomedical Center (BMC), Institute of Physiological Chemistry
  • Funding: since 2013

This research project deals with the role of RNA-binding proteins in the neurodegenerative diseases ALS (amyotrophic lateral sclerosis) and FTD (frontotemporal dementia). ALS and FTD are currently incurable diseases that inevitably lead to death within a few years. ALS is characterised by progressive muscle paralysis, while FTD is associated with changes in personality, language and social behaviour. In deceased ALS and FTD patients, characteristic protein deposits in the cytoplasm of nerve and glial cells are observed in histological examinations. The main components of the pathological deposits are two RNA-binding proteins, TDP-43 (TAR DNA binding protein of 43 kDa) and FUS (Fused in sarcoma), which are normally present in the nucleus and regulate transcription and splicing of a variety of target genes. My preliminary work as well as studies of other research groups have shown that a correctly functioning import of TDP-43 and FUS into the nucleus is essential for the survival of nerve cells and that the nuclear import of FUS is influenced by arginine methylation. However, several observations suggest that TDP-43 and FUS also leave the nucleus to play a role in cytosolic mRNA transport in neuronal extensions (dendrites). Defects in the nuclear export of TDP-43 and FUS, in the arginine methylation of FUS and in the dendritic transport of TDP-43 and FUS could lead to disturbed gene expression and thus contribute to the pathogenesis of ALS and FTD. However, the mechanisms of nuclear export of TDP-43 and FUS, the physiological function of arginine methylation of FUS and the exact function of the two proteins in dendritic mRNA transport are still unknown. My main goal is to understand how TDP-43 and FUS are exported from the nucleus, what is the biological function of arginine methylation of FUS, and what role TDP- 43 and FUS play in neuronal dendrites. I will identify the factors and signals that mediate the nuclear export of TDP-43 and FUS into the cytosol. In addition, I will address the question of how arginine methylation regulates nuclear import/export and influences the interaction of FUS with other proteins and RNAs. Finally, I will investigate which mRNAs are transported via TDP-43 and FUS into neuronal dendrites and whether the two proteins influence the translation of these mRNAs. The described experiments will provide new insights into the intracellular transport mechanisms and functions of two essential RNA-binding proteins. At the same time, they will answer the question of whether these processes are disrupted in ALS and FTD patients and thus contribute to the understanding of the pathomechanisms of these diseases.

Source: GEPRIS (Text), University Hospital (Picture)