Quality control and aggregation in an aging vertebrate proteome

09 Nov 2019
10:00 - 10:45

Quality control and aggregation in an aging vertebrate proteome

Age is the greatest risk factor for many neurodegenerative pathologies caused by protein aggregation. Yet because vertebrate model organisms have very long lifespans, examining the intersection of genetic risk factors with age has been extremely challenging. In particular, there are no proteomic experiments in complex model systems that permit the study of different organs and systemic cross-talk in a whole organism. To fill in these fundamental gaps in knowledge, we took advantage of the African turquoise killifish Nothobranchius furzeri, the shortest-lived vertebrate that can be bred in captivity. Over its 4-6 month lifespan this fish manifests age-dependent phenotypes and pathologies such as cognitive decline, loss of fertility, sarcopenia, and cancerous lesions. We established a robust protocol for isolating protein aggregates from fish tissues and performed a proteomic analysis of total protein and protein-aggregates in young and old fish alike. These experiments established tissue-specific patterns of proteostasis decline during aging. They also identified many vertebrate-specific proteins that have an increased propensity to aggregate with age, often in a tissue-specific manner. These changes in proteostasis and protein aggregation were accelerated in telomerase mutant animals with premature aging phenotypes. Many proteins that aggregated in an age-dependent manner harbor intrinsically disordered, prion-like domains and are linked to age-related degenerative diseases. Biochemical studies revealed that some of these proteins adopt an infectious, prion-like conformation in old tissues (e.g. the brain), but not in matched tissues from young animals. Taking advantage of the genetic and biochemical tractability of this model organism, across all life stages, we are now examining whether age-related decline in proteostasis and the aggregation of these intrinsically disordered proteins act as a driving forces in aging.