TDP-Assembly · Tuning TDP-43 self-assembly to understand physiological function and dysfunction

Neurodegenerative disorders are an enormous societal burden and we lack therapies that target these diseases at their origins. To develop therapies, we need to understand what goes wrong at the molecular level. I uncovered key mechanisms that cause RNA-binding proteins, such as TDP-43, to dysfunction and drive neurodegenerative processes. I discovered that RNA-binding proteins self-assemble into ribonucleoprotein granules that are the likely origins of RNA-binding protein aggregates. More recently, my group and I revealed aberrant phase transitions of condensed RNA-binding proteins occurring in disease and identified fundamental mechanisms by which such phase transitions are regulated in cells.In TDP-Assembly, I now want to find out why these proteins exhibit a self-assembly behavior that apparently risks pathological aggregation. My hypothesis is that self-assembly is essential for their many functions in gene regulation, and that different types of self-assemblies, e.g., small clusters or fluid or solid condensates, mediate different functions in cells. Using TDP-43 as a paradigm, I will test this hypothesis to ultimately understand the molecular basis of RNA-binding protein dysfunction in neurodegeneration.To achieve this goal, I will use synthetic biology approaches to rationally tune self-assembly of TDP-43 in cells. I will study how altered TDP-43 self-assembly affects its known molecular functions, i.e., regulation of transcription, alternative splicing, and translation. Transcriptome and proteome analyses will draw a systems biology map of altered TDP-43 self-assembly and might lead us to novel functions of TDP-43 self-assembly. Ultimately, I will address how TDP-43's self-assembly, and thus its functions, are altered by disease-linked mutations in neuronal cells.TDP-Assembly will forge a new understanding of the functional and pathological relevance of RNA-binding protein self-assembly and might inspire new therapies that target self-assembly processes.