# Role of RAN peptides in polyQ-independent toxicity in a new C. elegans model for Huntington’s disease

> **NIH NIH R21** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $185,893

## Abstract

Several neurodegenerative disorders, including Huntington’s disease (HD), are caused by the
expansion of a CAG nucleotide repeat. For many years, it has been hypothesized that the
translation of this CAG sequence into a poly-glutamine (polyQ) protein represents the molecular
basis for these diseases. However, in some cases, patients carrying expanded CAG repeats
exhibit significant neurodegeneration in the absence of detectable polyQ protein, suggesting other
polyQ-independent mechanisms might contribute to HD. The nature of such polyQ-independent
toxicity in CAG repeat disorders is unknown. Recent work demonstrated that Huntington’s
associated CAG repeats can undergo an unusual type of translation called Repeat Associated
non-AUG-dependent (RAN) translation. In RAN translation, both sense (CAG)x and antisense
(CTG)x repeats are translated in all three reading frames to produce five distinct RAN peptides.
RAN peptides are detected in HD patients with CAG repeat expansions but not in control patients
that lack expansions. Several RAN peptides are present in brain regions that undergo
neurodegeneration in HD but that lack detectable polyQ, suggesting that RAN peptides make
significant polyQ-independent pathological contributions to HD. To better understand the
pathological potential of HD RAN peptides, we generated C. elegans models for each individual
RAN peptide. We found that several RAN peptides form protein aggregates that are distinct from
well-described polyQ aggregates. At least one of these new RAN peptides exhibits toxicity that
rivals that of polyQ when expressed in C. elegans. In this project, we will use the significant
experimental advantages of C. elegans to rapidly characterize these new HD RAN peptides and
determine if they share similar mechanisms of toxicity with the better understood polyQ proteins.
Our studies will define clinically relevant mechanisms that facilitate HD RAN peptide neurotoxicity,
some of which might be leveraged to treat or better diagnose this currently incurable diseases.

## Key facts

- **NIH application ID:** 9853070
- **Project number:** 5R21NS107797-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** SAMUEL T LAMITINA
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $185,893
- **Award type:** 5
- **Project period:** 2019-02-01 → 2021-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9853070

## Citation

> US National Institutes of Health, RePORTER application 9853070, Role of RAN peptides in polyQ-independent toxicity in a new C. elegans model for Huntington’s disease (5R21NS107797-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9853070. Licensed CC0.

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