# Metabolic perturbations as a modifier of repeat-associated non-AUG translation in C9orf72-linked ALS/FTD

> **NIH NIH F31** · THOMAS JEFFERSON UNIVERSITY · 2020 · $45,520

## Abstract

PROJECT SUMMARY
Metabolic perturbations as a modifier of repeat-associated non-AUG translation in C9orf72-linked ALS/FTD
The -(GGGGCC)n- hexanucleotide repeat expansion (HRE) occurring in the C9orf72 (C9) gene is the most common cause
of ALS and FTD and leads to the production of neurotoxic dipeptide repeat proteins (DPRs) by a noncanonical mechanism
known as repeat-associated non-AUG (RAN) translation. Activation of the integrated stress response by a number of
different cellular stressors has been shown to increase the occurrence of RAN translation without increasing the canonical
AUG-driven translation. The core event in the ISR activation is phosphorylation of the α subunit of eukaryotic initiation
factor 2 (eIF2α) by one of four kinases: PERK, PKR, GCN2, and HRI, each of which can be activated by different cellular
stressors. I propose to address the role of metabolic perturbations and their potential modifier effect on C9-linked RAN
translation. This could occur via activation of the ISR, specifically through the GCN2 and PERK pathways, which are
activated by amino acid deprivation and ER stress, respectively. This is particularly relevant to understanding C9-ALS/FTD
pathogenic mechanisms because a variety of metabolic perturbations, including hypermetabolism, glucose/energy
deficiency, and alterations to the mitochondrial respiratory chain, are observed in ALS and could lead to ISR activation. For
instance, glucose deficiency in neurons could force cells to metabolize amino acids for energy, potentially causing a deficit
in amino acid (a.a.) supply and activating the ISR via GCN2. Likewise, perturbations to the respiratory chain could cause
excessive ROS formation, leading to ER stress and activating the ISR via PERK. I propose to test the hypothesis that in C9-
ALS/FTD, disease-driven energy imbalances promote RAN translation via ISR activation. I will employ both in vitro and
in vivo models of the disease, including cortical and motor neurons differentiated from C9 patient-derived induced
pluripotent stem cells (C9-iPSCs) as well as a C9orf72 bacterial artificial chromosome (BAC) transgenic mouse model. I
will perturb the energy balance in these models by targeting critical metabolic pathways. Then I will evaluate the impact on
ISR activation and RAN translation using biochemical, molecular and cell biology techniques and several behavioral
analyses.

## Key facts

- **NIH application ID:** 10067825
- **Project number:** 1F31NS118838-01
- **Recipient organization:** THOMAS JEFFERSON UNIVERSITY
- **Principal Investigator:** Andrew Nelson
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $45,520
- **Award type:** 1
- **Project period:** 2020-09-17 → 2022-09-16

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10067825

## Citation

> US National Institutes of Health, RePORTER application 10067825, Metabolic perturbations as a modifier of repeat-associated non-AUG translation in C9orf72-linked ALS/FTD (1F31NS118838-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10067825. Licensed CC0.

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