# Mechanisms of chimeric DPR production and toxicity in c9ALS/FTD

> **NIH NIH R01** · EMORY UNIVERSITY · 2024 · $654,423

## Abstract

PROJECT SUMMARY/ABSTRACT
 Expanded GGGGCC (G4C2) hexanucleotide repeats in the C9orf72 gene were recently identified as the most
common genetic cause of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD), two
neurodegenerative disorders with genetic and pathological overlap. Despite being located in a non-coding region
of the gene, expanded G4C2 repeats can promote translation in both the sense and antisense direction to produce
five different aggregating dipeptide repeat proteins (DPRs) which are thought to play a key role in c9ALS/FTD
pathogenesis. Translation across the expanded repeats has been proposed to be mediated primarily by two, not
necessarily mutually exclusive, non-canonical translation mechanisms: repeat-associated non-AUG (RAN)
translation and/or ribosomal initiation at an upstream near-cognate CUG codon.
 Recently, we have demonstrated that DPRs are produced in a second, hexanucleotide repeat expansion
disorder, spinocerebellar ataxia type 36 (SCA36). Given the genetic similarity between the TG3C2 and G4C2
repeats underlying SCA36 and c9ALS/FTD, respectively, poly(GP) and poly(PR) DPRs are produced in both
disorders. However, poly(GP) DPRs in SCA36 are soluble species and do not form the characteristic cytoplasmic
inclusions seen in c9ALS/FTD suggesting that aggregation of the intrinsically soluble poly(GP) species is
mediated through an alternate mechanism in c9ALS/FTD. It has generally been accepted that independent
translational events with unique open reading frames give rise to individual, homogenous DPR species.
However, a growing body of evidence suggests that frameshifting events, either through ribosomal frameshifting
or frameshifting indels, can occur across expanded repeat sequences, thereby expanding the possibility of
complex DPR species. Indeed, data from our group show that heterogenous chimeric DPR proteins (cDPRs),
composed of aggregate prone poly(GA) and poly(GP) or poly(GR) are detectable in c9ALS/FTD patient tissue.
 These cDPR species alter the localization and solubility of homogenous DPR species. However, to what
extent these chimeric DPRs (cDPRs) contribute to disease pathogenesis is unknown. Based on our preliminary
findings, it is our central hypothesis that cDPRs are detectable throughout the central nervous system (CNS)
and that cDPRs can modify the toxicity of homogenous DPR species. To test this hypothesis, we will 1) identify
complexity, extent, and mechanism of cDPR pathology in c9ALS/FTD, 2) identify the molecular consequences
and neuronal toxicity of poly(GA:GR) cDPRs in vitro and in vivo , and 3) develop a novel GA:GR cDPR mouse
that more faithfully recapitulates human pathology. Results from this proposal will expand our understanding of
DPR biology and provide new insight into the cellular cascades that cause neurodegeneration in c9ALS/FTD.

## Key facts

- **NIH application ID:** 10885356
- **Project number:** 1R01NS137434-01
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Zachary Thomas McEachin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $654,423
- **Award type:** 1
- **Project period:** 2024-07-01 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10885356

## Citation

> US National Institutes of Health, RePORTER application 10885356, Mechanisms of chimeric DPR production and toxicity in c9ALS/FTD (1R01NS137434-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10885356. Licensed CC0.

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