RNA-binding proteins in neurodegenerative diseases: Transport processes and pathomechnisms

• Applicant: Professorin Dr. Dorothee Dormann
• Subject Area: Experimental Models for the Understanding of Nervous System Diseases ; Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2013 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 246137224

This research proposal is concerned with the role of RNA-binding proteins in the pathogenesis of the neurodegenerative diseases ALS (amyotrophic lateral sclerosis) and FTD (frontotemporal dementia). ALS and FTD are currently incurable, and affected patients usually die within a few years of disease onset. ALS is mainly characterized by progressive muscle paralysis, whereas FTD is hallmarked by progressive changes in personality, language and social behavior. Histologial examinations have revealed characteristic protein inclusions in the cytosol of neurons and glia cells in post-mortem brains of ALS and FTD patients. The main components of these pathological inclusions are two RNA-binding proteins, TDP-43 (TAR DNA binding protein of 43 kDa) and FUS (Fused in sarcoma), which usually reside in the cell nucleus and regulate transcription and splicing of numerous target genes.My previous work and work by others has shown that proper nuclear import of TDP-43 and FUS is crucial for neuronal health and that nuclear import of FUS is modulated by arginine methylation. However, there are indications that TDP-43 and FUS exit the nucleus again, in order to mediate mRNA transport in neuronal dendrites. Defects in nuclear export of TDP-43 and FUS, in arginine methylation of FUS, as well as in dendritic transport of TDP-43 and FUS could lead to disturbed gene expression and thus contribute to 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 role of TDP-43 and FUS in dendritic mRNA transport are currently unknown. My overall goal is to understand how TDP-43 and FUS are exported from the nucleus, what the biological function of arginine methylation of FUS is, and what role the two proteins play in neuronal dendrites. To this end, I will identify the factors and signals that mediate nuclear export of TDP-43 and FUS. Moreover, I will study how arginine methylation regulates nuclear import/export as well as protein and RNA interactions of FUS. Finally, I will investigate which mRNAs are transported by TDP- 43 and FUS in neuronal dendrites and if the two proteins affect translation of these mRNAs. The proposed experiments will provide new insights into the intracellular transport mechanisms and function of two essential RNA-binding proteins. Moreover, they will reveal if these processes are pathologically altered in ALS and FTD patients and thus will contribute to our understanding of the pathomechanisms of these diseases.

• DFG Programme: Independent Junior Research Groups