Project Grant R37AG100304

CHEMICAL MODULATION OF PROTEOSTASIS TO PROMOTE LONGEVITY AND HEALTHY AGING - ABSTRACT NEURONAL PROTEOSTASIS IS ESSENTIAL FOR BEHAVIORAL AS WELL AS PHYSIOLOGICAL HEALTH FOR ANY METAZOAN. PROTEOSTASIS ENSURES THAT PROTEINS ARE CORRECTLY FOLDED, FUNCTIONAL, AND DEGRADED WHEN DAMAGED OR NO LONGER NEEDED. NEWLY SYNTHESIZED PROTEINS PRODUCED BY THE RIBOSOME DELIVER THE BIGGEST PROTEIN-FOLDING LOAD TO THE PROTEOSTASIS MACHINERY AND ARE THE PROTEIN SPECIES MOST VULNERABLE TO MISFOLDING. CONSEQUENTLY, PROTEIN SYNTHESIS BY RIBOSOMES MUST BE CAREFULLY CONTROLLED TO PREVENT THE PRODUCTION OF FAULTY OR EXCESS PROTEINS THAT COULD OVERWHELM CELLULAR QUALITY CONTROL SYSTEMS. PROTEOSTATIC CAPACITY DECLINES WITH AGE. WE HYPOTHESIZE THAT IT MIGHT BE POSSIBLE TO FREE UP FOLDING CAPACITY IN OLD ANIMALS BY LOWERING PROTEIN SYNTHESIS, THEREBY REDUCING THE FOLDING LOAD AND REDUCING THE DANGER OF PROTEIN MISFOLDING AND AGGREGATION. IN SMALL MODEL ORGANISMS, LOWERING PROTEIN SYNTHESIS DELAYS AGING AND EXTENDS LIFESPAN. HOWEVER, IN MAMMALS, LOWERING TRANSLATION TO IMPROVE NEURONAL PROTEOSTASIS IS CHALLENGING, AS TRANSLATION IS CENTRAL TO THE ABILITY OF THE BRAIN TO FORM MEMORIES. OUR DATA SUGGEST THAT POLYSOME-MEDIATED TRANSLATION POSES A PARTICULAR CHALLENGE FOR PROTEOSTASIS AND THAT A SIGNIFICANT FRACTION OF AGGREGATION-PRONE PROTEINS ARE POLYSOME-TRANSLATED. THIS INSIGHT SUGGESTS THAT IT MIGHT BE SUFFICIENT TO LOWER POLYSOME-MEDIATED TRANSLATION TO FREE UP PROTEOSTATIC CAPACITY IN AGING ANIMALS. BECAUSE MANY NEURON-SPECIFIC MRNAS ARE MONOSOME-TRANSLATED, SELECTIVE INHIBITION OF POLYSOME-MEDIATED TRANSLATION IS UNLIKELY TO BLOCK MEMORY FORMATION. TO STUDY THE ROLE OF POLYSOME-MEDIATED TRANSLATION IN PROMOTING PROTEIN AGGREGATION IN THE AGING BRAIN IN VIVO, WE GENERATED CHEMICAL AND COMPUTATIONAL TOOLS TO ATTENUATE POLYSOME-MEDIATED TRANSLATION IN VIVO, QUANTIFY PROTEIN CONFORMATIONAL CHANGES ACROSS THE NEURONAL PROTEOME WITH AGE, AND QUANTIFY HEALTHY AGING AND BEHAVIOR IN LONGITUDINAL STUDIES. WE WILL USE THOSE TOOLS TO DETERMINE IF ATTENUATION POLYSOME- MEDIATED TRANSLATION IS SUFFICIENT TO REDUCE PROTEIN AGGREGATION IN THE AGING BRAIN AND TO PROMOTE HEALTHY AGING AND LIFESPAN.