Project Summary People are living longer, which increases their risk of developing neurodegenerative disorders. Such disorders can be characterized by the accumulation and aggregation of specific proteins in the brain. These aggregates often contain protein fragments produced by increases in protein cleavage or defects in protein quality control systems such as regulated protein degradation. Our overall goal is to understand the effects of protein aggregates on normal cell function and to identify cellular pathways that prevent toxicity. Previously we found that the N-termini of fragments associated with neurodegenerative disorders influence their metabolism, tendency to aggregate, and the morphology of their aggregates. We also reported that specific fragments of the TAR DNA Binding Protein 43 (TDP43) could be degraded either by the N-degron pathway or through a Bcl-2-associated athanogene 6 (BAG6)-mediated fashion depending upon the extent of fragment hydrophobicity. The studies proposed in this supplement will evaluate the level of cooperativity between BAG6 and the N- degron pathway to protect cells from intracellular aggregation associated with neurodegeneration. It will also examine whether this cooperatively results in the triaged removal of toxic proteins. This will provide novel insight into how cells are protected from toxicity associated with neurodegeneration. Finally, this sub-project is proposed as a Diversity Supplement to expand Aim 1 of the Parent R15 and to serve as a training vehicle for graduate student Winnie Lokuso.