Uncovering an Enzymatic Program that Drives Physiological and Pathological Amyloid Formation.

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Project Summary Amyloids are β-sheet rich aggregates that accumulate in various proteinopathies. This correlation has led to the association of amyloids with the diseased state. However, organisms across biology utilize amyloids without any apparent detrimental effects. This raises the fundamental question; how do cells assemble non-toxic amyloids as needed? Our lab uncovered an inducible program of physiological amyloidogenesis that converts Nucleoli into Amyloid-bodies. While investigating these amyloid-enriched, solid-like condensates, we identified that Terminal End Nucleotidyltransferase 4b (TENT4b) stimulated the conversion of amyloidogenic liquid-to-solid phase transition. Our preliminary results indicate that TENTs catalyze unusually long poly(A)-rich tails to drive amyloidogenesis. These low-complexity RNA molecules act as linear polyanionic cofactors that stimulate amyloidogenesis. This activity is inhibited by the RNA exosome which degrades tailed RNA. In addition to physiological amyloidogenesis, TENTs also catalyze pathological amyloidogenesis which exhausts toxic oligomeric intermediates in Alzheimer’s and Parkinson’s disease models. Depletion of the RNA exosome that antagonizes TENTs, delays age-associated proteotoxicity in these disease models. These results suggest the following hypothesis for this K99:R00 application: The RNA tailing machinery drives amyloidogenesis to protect against toxic oligomeric intermediates. We plan to test this hypothesis by: Aim 1- investigating the mechanism that drives physiological amyloidogenesis and Aim 2- testing if this machinery protects against pathological amyloid toxicity. This research program reveals the provocative concept that cells possess enzymes dedicated to making non-toxic amyloids, highlighting that cellular amyloidogenesis is an actively controlled process. The cellular use of RNA to actively control protein folding bridges unrelated fields of research and offers new approaches to combat amyloid based disease.