# Conserved regulation of proteostasis by post-translational protein AMPylation

> **NIH NIH R35** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2022 · $384,099

## Abstract

ABSTRACT
The primary goal of this MIRA R35 application is to understand the molecular basis and mechanisms by which
protein AMPylation regulates proteostasis in normal physiology and in the context of protein aggregation-
associated diseases. Protein AMPylation is conferred by dedicated AMPylases, which are present in a single
copy in most metazoans. These enzymes are increasingly recognized to control proteostasis, modulating how
and when amyloidogenic proteins – such as amyloid-β (Aβ), α-synuclein (α-Syn) and poly-glutamine repeat
proteins – aggregate. However, our knowledge of AMPylase regulation, target preference and their roles in
physiological as well as in disease states remains elusive. Closing these gaps in knowledge is key for gaining
fundamentally important insights into how post-translational protein AMPylation controls proteostasis, and will
potentially enable the development of therapeutic interventions that capitalize on this process. The goals of this
proposal are to 1) Dissect the mechanistic and physiological impact of FIC-1/FICD-mediated protein
AMPylation on proteostasis, and 2) elucidate the mechanistic basis of protein AMPylation in the cytoplasm and
nucleus. We will use a multi-faceted, translational and multi-organism approach to address the genetics and
biochemistry associated with these central questions in protein aggregation and proteostasis regulation. Our
research program is utilizing four complementary model systems: the nematode C. elegans, purified proteins
for in vitro biochemistry, human cell lines and in vivo mouse models, each offering its unique set of advantages
to examine protein AMPylation in the context of health and disease. We will leverage our unique in vivo and in
vitro assays and tools, while continuing to design novel approaches, to define the enzymes, targets, signaling
cascades and biological processes involved in AMPylation-mediated proteostasis regulation in unpreceded
details. In the next five years, our goal is to fully develop current projects and to devise new tools and
techniques to continuously produce genetic and mechanistic data with translational potential. A mechanistic
understanding of these processes will advance our knowledge of protein folding and proteostasis pathways
which will represent key steps towards the discovery of novel interventions to prevent or treat protein
aggregation-associated disorders.

## Key facts

- **NIH application ID:** 10488606
- **Project number:** 5R35GM142561-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Matthias Christof Truttmann
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $384,099
- **Award type:** 5
- **Project period:** 2021-09-15 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10488606

## Citation

> US National Institutes of Health, RePORTER application 10488606, Conserved regulation of proteostasis by post-translational protein AMPylation (5R35GM142561-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10488606. Licensed CC0.

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