This R35 proposal builds on the principal investigator’s longstanding success seeking the causes of age- related neurodegenerative diseases and developing treatments for these devastating and largely fatal disorders. The proposal’s unifying theme is a focus on proteins that participate in ubiquitin-linked quality control pathways and that are prone, in neurodegenerative diseases, to phase-separate and aggregate. Building on our recent discoveries in polyglutamine-mediated neurodegeneration and brain-expressed ubiquilins (a class of proteins implicated in various neurodegenerative diseases), we will apply multi-scalar approaches to define pathogenic mechanisms, emphasizing intersections with ubiquitin-dependent pathways in the search for novel therapeutic targets. The importance of ubiquitin in the nervous system extends far beyond its classically defined degradative role in the ubiquitin-proteasome system. But how the broader ubiquitin signaling system is impaired by, or activated in response to, diseases of the nervous system represents a significant gap in current knowledge. Leveraging a broad suite of innovative tools/models and an exceptional research environment, we will address fundamental issues of broad relevance to age-related neurodegeneration. These topical issues include: the impact of altered ubiquitin signaling in the nucleus; the contribution of altered ubiquitin homeostasis to selective cell type and regional vulnerability; and the relationship between mutation-induced changes in phase transitions undertaken by disease proteins, altered function in ubiquitin-linked pathways, and toxicity in the nervous system. The discoveries we make through the R35 will help define the complex biological roles of ubiquitin in diseases of the nervous system, highlight potential shared elements of disease pathogenesis, and identify promising therapeutic targets that could drive the development of treatments for neurodegenerative disorders.