Contact PD/PI: Cingolani, Gino Project Summary Protein aggregation underlies several neurodegenerative diseases and is a pathological hallmark of Amyotrophic Lateral Sclerosis (ALS). In this devastating disease, cytoplasmic inclusions containing aggregated, often hyper post-translationally modified proteins are found in degenerating motor neurons and surrounding oligodendrocytes. There is no specific pharmacological treatment to prevent protein aggregation or promote disaggregation and clearance of existing aggregates that drive the progression of neurodegeneration. This exploratory R21 proposal builds upon the recent discovery that nuclear import factors of the importin β-superfamily can exert disaggregase activity toward other proteins. Combining the power of protein biochemistry and structural biology with our know-how in nucleocytoplasmic transport, we seek to learn from importins the biological principles for disaggregase activity and use this knowledge to design more versatile protein therapeutics. We believe that the high-risk, high-reward R21 funding mechanism will fuel the creative and diligent pursuit of answers to difficult biological questions, permitting our research program to achieve significant advancements in developing novel protein therapeutics that reduce pathogenic protein aggregation. Project Summary/Abstract Page 6