PROJECT SUMMARY/ABSTRACT The aggregation of misfolded proteins is a prominent pathological feature in most age-related neurodegenerative diseases. This includes Huntington's disease (HD) and various spinocerebellar ataxias, inherited diseases caused by expanded, aggregation-prone polyglutamine (polyQ) stretches in specific proteins. Understanding how cells prevent the misfolding of these mutant polyQ proteins holds the potential to reveal therapeutic strategies not only for polyQ disorders but also for other neurodegenerative conditions. I conducted large-scale CRISPR screens for modifiers of polyQ protein aggregation in human cells that revealed DNAJC7, an Hsp40 co-chaperone, as a top hit. Molecular chaperones are a diverse group of proteins that assist in proper protein folding, but we lack knowledge about the specific endogenous chaperones most effective in preventing polyQ protein aggregation, along with their roles in neurons. Importantly, DNAJC7 is highly expressed in neurons and has connections to other neurodegenerative diseases, leading to the central hypothesis of this proposal: DNAJC7 is a key neuronal Hsp40 capable of selectively inhibiting aggregation of amyloidogenic proteins, including mutant polyQ proteins. Aim 1 of this proposal will investigate the impact of DNAJC7 expression on disease phenotypes in neuronal models of HD, while Aim 2 will delve into DNAJC7’s mechanism and range of selectivity for different amyloidogenic disease proteins. My long-term goal is to establish myself as an academic neuropathologist with a research program dedicated to studying neuronal protein homeostasis pathways in neurodegeneration. This proposal outlines a comprehensive 5-year mentored career development plan that will provide me the essential knowledge and scientific training necessary to successfully transition to this goal. The training plan includes acquiring various new skills in cutting-edge techniques spanning microscopy, CRISPR functional genomics in iPSC neurons, and proteomics, as well as enhancing skills in bioinformatics and statistics. Additionally, the training plan covers the development of professional skills needed to successfully launch and manage a laboratory, including scientific communication, grant writing, and lab management. To achieve these objectives, I have assembled a multidisciplinary mentorship team with complementary expertise, and includes Dr. Martin Kampmann (mentor), Dr. Eric Huang (co-mentor), and advisory members Dr. Jason Gestwicki, Dr. Steven Finkbeiner, Dr. Lea Grinberg, and Dr. Arun Wiita. UCSF provides an exceptional research environment, equipped with cutting-edge technologies and a range of leaders across multiple disciplines. This proposal will empower me with the necessary skills to establish a thriving and rigorous independent laboratory, merging with my neuropathology training to become a leader in neurodegenerative disease research.