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

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
 
Final Report Year 2024

Final Report Abstract

This research project was concerned with the role of RNA-binding proteins in the pathogenesis of neurodegenerative diseases, such as 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. Brains of ALS and FTD patients feature characteristic protein aggregates in the cytosol of neurons and glia cells, whose main components are the RNA-binding proteins TDP-43 and FUS. In our project, we aimed to unravel molecular mechanisms that cause TDP-43 and FUS to mislocalize and aggregate, as such an understanding will be important for developing therapeutic strategies to counteract or reverse RNA-binding protein dysfunction and neurodegeneration. Our previous work had shown that proper nuclear import of FUS and TDP-43 is crucial for neuronal health and that specific nuclear import receptors function in nuclear import and chaperoning of the aggregation-prone RNA-binding proteins, thus preventing their phase separation and aggregation in the cytoplasm. Here we could demonstrate that FUS is chaperoned by a network of nuclear import receptors and that diverse import receptors can also directly bind arginine-rich repeat proteins that arise in genetic forms of ALS/FTD and shield them from pathological interactions with various cellular components. Moreover, we examined how post-translational modifications cooperate to regulate nuclear import and aggregation of RNA-binding proteins. Our previous work had shown that post-translational methylation of arginines suppresses phase separation and aggregation of FUS. Here we now demonstrate that arginines can be post-translationally converted to citrulline by the enzyme PAD4, thus reducing nuclear import and phase separation / aggregation of FUS. Moreover, we found that arginines in RG regions of FUS are crucial for FUS’ ability to bind and process specific cellular RNAs. Last, we studied disease-associated phosphorylation sites on TDP-43 and found that this post-translational modification antagonizes TDP-43’ phase separation and aggregation, suggesting that it may be a cellular response mechanism to keep TDP-43 in a soluble, functional state. Taken together, we discovered novel cellular quality control mechanisms that antagonize pathological mislocalization and aggregation of disease-linked RNA-binding proteins, thus providing new insights into the molecular basis of neurodegenerative disorders.

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