Disentangling the diverse forms of collective protein homeostasis in neuronal condensates (360G-Wellcome-340926_Z_25_Z)

This project will interrogate interstasis, a mechanism for collective dosage regulation of co-condensing proteins that contain specific types of intrinsically disordered regions (IDRs). Interstasis involves a collective feedback loop, where mRNAs that encode for the co-condensing proteins are captured into the same condensate as these proteins. As a proof-of-concept, we demonstrated how interstasis at nuclear speckles collectively regulates the proteins with mix-charged IDRs by capturing their own mRNAs into speckles. Here we will assess whether similar feedback loops regulate additional types of IDR-containing proteins in various condensates. We will identify key RNA- binding proteins and RNA signatures that are important for each type of interstasis. Ultimately, we will determine the biological roles of interstasis in the context of various physiological shifts, stress responses and aging. We’ll use small molecule screening to determine the cellular pathways that can modulate interstatic mechanisms, and will thereby study the crosstalk between RNA and protein-mediated proteostatic pathways. Finally, we will combine genetic and environmental variation in neurons to assess the functions of interstasis in protection from stress and aging, and to demonstrate its physiologic roles in protein homeostasis.