Cold Spring Harbor Laboratory Conference on Protein Homeostasis in Health and Disease April 21 – 25, 2020 ABSTRACT This proposal is a request for financial support for a meeting on PROTEIN HOMEOSTASIS IN HEALTH AND DISEASE to be held at Cold Spring Harbor Laboratory from April 21 – 25, 2020. This meeting is the premier international forum for presentation of new results in this area, and is attended by representatives from virtually every major laboratory in the field. The explosion of new information on how the folded state of proteins is acquired and maintained in vivo and the relevance of this process to healthy aging and risk for diseases of neurodegeneration, cancer, and metabolism guarantees an excitement and urgency of this meeting. Because of the recent developments on stress signaling in aging and disease, we will open the meeting with this new session followed the next day with a session on protein aggregation in aging and neurodegenerative diseases and then closing the meeting with a session on correcting proteostasis in aging and disease. Additional sessions will address the relationship between protein synthesis, folding, translocation and degradation by discussing the molecular mechanisms of chaperone function, degradative mechanisms and on spatial quality control and organellar proteostasis. The meeting will also introduce another new session on stress granules and phase transitions that has brought many new concepts on stress physiology, regulatory biology and novel forms of macromolecular interaction. These fundamental questions are at the heart of biology of proteostasis that will be complemented by the sessions on aging and proteostasis failure in diseases of protein misfolding including Alzheimer's disease, ALS, Parkinson's disease and Huntington's disease. The themes of aging, proteostasis failure, and diseases of protein misfolding are well integrated throughout the meeting, and emerging principles on protein client interactions and alternate protein conformations will be predominantly displayed. The diverse protein quality control strategies used by compartments of the cell to ensure the integrity of the secretory and organellar pathways during times of protein folding stress will be represented by emerging topics on spatial quality control within a cell. The field of heat shock proteins and molecular chaperones has grown exponentially and draws interest not only from traditional scientific disciplines in the basic sciences but also from diverse areas of biomedical research including neurodegenerative disease, infectious diseases, cancer, heart disease and aging. The meeting will have eight lecture sessions, two poster sessions, two rapid-fire presentation sessions, and a panel discussion on scientific publishing. The sessions include: 1) Integrative stress signaling in aging and disease, 2) Chaperone mechanisms I, 3) Protein aggregation in aging and neurodegenerative diseases, 4) Clearance mechanisms, 5) Chaperone mechanisms II, 6) Stress granules and phase transitions, 7) Organellar proteostasis and spatial quality control, and 8) Correcting proteostasis in aging and disease. Each session will consist of eight to nine oral presentations and will be chaired by an invited speaker. Generally, two speakers will be pre-invited per session with the remainder to be selected from submitted abstracts, thus ~60-65% of speakers will be from submitted abstracts to ensure balance of junior investigators, women and all forms of diversity. As well, we will have two rapid fire sessions, each with ten-2 min. talks to increase the visibility from the poster sessions. This balance of talks allows the meeting to feature presentations by leading scientists, to be responsive to exciting new developments, and to encourage diverse participation that recognizes new investigators.

Cold Spring Harbor Laboratory Conference on Protein Homeostasis in Health and Disease April 21 – 25, 2020 PROJECT NARRATIVE Proteins are composed of polymers of amino acids (or polypeptides) and execute essential tasks in all living organisms. Protein function is critically dependent on the folding of their constituent polypeptides into active three-dimensional objects through the interactions of molecular chaperones. Protein homeostasis is achieved by balanced synthesis, folding, translocation and degradation of proteins. Experimental evidence accumulated in the recent past has revealed that failure of this process (protein misfolding) in aging leads to some of the most devastating diseases affecting humanity. The latter include common neurodegenerative disorders, such as Parkinson's Disease and Alzheimer's Disease, common metabolic disorders such as Diabetes Mellitus and a host of other conditions liked to the aging process. The Cold Spring Harbor Meeting on Protein Homeostasis in Health and Disease brings together experts in diverse aspects of protein folding, the cellular response to protein misfolding and diseases and therapeutic approaches for age-associated diseases of protein conformation. As such it serves as the premier clearinghouse for ideas on how to eventually translate the basic discoveries in the area to future treatments of recalcitrant diseases.