# Elucidating the impact of FIC-1/FICD-mediated AMPylation on polyglutamine aggregation dynamics and toxicity

> **NIH NIH F31** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2022 · $39,531

## Abstract

PROJECT SUMMARY
Huntington’s disease (HD) and spinocerebellar ataxia type 3 (SCA3) are inherited aging-associated diseases
that have a devastating impact on patients and family caretakers relative to their prevalence in the general
population. These conditions belong to a family of polyglutamine (polyQ) expansion diseases caused by
mutations resulting in the pathological expansion of trinucleotide (CAGn) repeats in distinct genes. Increases in
CAG repeat length give rise to proteins containing aberrantly expanded polyQ tracts, which interfere with normal
protein function and promote misfolding. Toxicity in these diseases is thought to arise in part from the formation
of pathological inclusion bodies comprised of aberrantly conformed mutant proteins, a hallmark observed in
numerous aging-associated neurodegenerative diseases. Despite extensive efforts to decipher the mechanisms
underlying toxicity in polyQ diseases, however, little progress has been made towards identifying targets for
therapeutic intervention.
Recently, the post-translational modification (PTM), AMPylation, has emerged as a novel regulator of HSP70
family chaperones, crucial components of the cell’s protein quality control machinery that buffer against protein
misfolding stress. Protein AMPylation is carried out by the fic-type AMPylase, FICD in humans, and its ortholog
FIC-1, in C. elegans, respectively. Work in our lab has established that FIC-1-mediated AMPylation directly alters
polyQ aggregation dynamics and toxicity. Further, my preliminary data as presented in this proposal identifies
fic-1 deficiency as sufficient to rescue survival of C. elegans expressing aggregation-prone polyQs during
development in a polyQ length-dependent manner. Taken together, these findings suggest that the loss of FIC-
1/FICD-mediated AMPylation bolsters proteostasis network capacity to alleviate toxicity induced by polyQ protein
aggregation.
This project will utilize cross-disciplinary approaches to generate a holistic characterization of FICD/FIC-1-
mediated AMPylation in polyQ diseases. To this end, I will harness the powerful genetics of C. elegans to uncover
novel pathway(s) that promote survival in the face of pathogenic polyQ aggregation (Aim 1). In tandem, I will
employ functional assays in neurons derived from HD and SCA3 patient stem cells to profile how FICD activity
affects polyQ aggregation and toxicity in these disease models (Aim 2). The results of these studies will advance
our knowledge of how AMPylation regulates proteostasis in polyQ diseases. The ultimate goal of my research is
to capitalize on these findings to develop translatable therapeutic approaches for aging-associated diseases.

## Key facts

- **NIH application ID:** 10464265
- **Project number:** 1F31NS127485-01
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Kate Matthys Van Pelt
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $39,531
- **Award type:** 1
- **Project period:** 2022-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10464265

## Citation

> US National Institutes of Health, RePORTER application 10464265, Elucidating the impact of FIC-1/FICD-mediated AMPylation on polyglutamine aggregation dynamics and toxicity (1F31NS127485-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10464265. Licensed CC0.

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