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

> **NIH NIH K99** · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · 2024 · $93,394

## Abstract

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.

## Key facts

- **NIH application ID:** 10757458
- **Project number:** 5K99AG080474-02
- **Recipient organization:** UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
- **Principal Investigator:** Michael Bokros
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $93,394
- **Award type:** 5
- **Project period:** 2023-01-01 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10757458

## Citation

> US National Institutes of Health, RePORTER application 10757458, Uncovering an Enzymatic Program that Drives Physiological and Pathological Amyloid Formation. (5K99AG080474-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10757458. Licensed CC0.

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