# Novel repeat associated non-AUG (RAN) proteins in sALS, sFTD and SBMA: shared pathological features and unifying therapeutic opportunities

> **NIH NIH RF1** · UNIVERSITY OF FLORIDA · 2022 · $1,930,065

## Abstract

ABSTRACT
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are complex neurodegenerative
diseases that affect motor neurons in various regions of brain and spinal cord with devastating impacts on a
patient’s health and lifespan. While research has identified ALS and FTD mutations in a number of genes (i.e.
C9orf72, MAPT, SOD, and GRN), approximately 90% of ALS and 60% of FTD patients present as sporadic
cases (sALS & sFTD) with unknown genetic etiology. Complex disease mechanisms coupled with a large
genetically and phenotypically heterogeneous patient population have severely limited research and
therapeutic success for these diseases. The discovery of the intronic C9orf72 G4C2 repeat expansion mutation
as the most common genetic cause of ALS and FTD links these diseases to the larger family of microsatellite
expansion disorders. Amongst these diseases is spinal-bulbar muscular atrophy (SBMA), a CAG•CTG disease
that, like ALS and FTD, also affects motor neurons. A growing number of expansion disorders are reported to
express proteins in multiple reading frames by repeat associated non-AUG (RAN) translation. Our recent
unpublished findings show that novel polySer and polyLeu RAN proteins accumulate in at least six of the ten
CAG•CTG polyGln diseases. These observations raise the possibility that novel polySer and polyLeu RAN
proteins accumulate in the spinal-bulbar muscular atrophy (SBMA) and that other unidentified RAN proteins
may contribute to sALS and sFTD. Our central hypothesis is that repeat expansion mutations that express
novel RAN proteins substantially contribute to sALS, sFTD and spinobulbar muscular atrophy (SBMA) and that
therapeutic approaches that reduce RAN protein levels will improve disease in preclinical models. To address
this hypothesis, we have developed an innovative pathology-to-genetics strategy that enables rapid and direct
identification of novel RAN protein producing expansion mutations from patient DNA. We are excited to report
that in an initial screen, ~30% of sALS autopsy cases of unknown genetic etiology (i.e. C9 and SCA36
negative) were positive for GR or PR RAN protein aggregates suggesting the presence of novel expansion
mutations. In this proposal, we will test the hypothesis that novel types of RAN proteins contribute to sALS,
sFTD and SBMA (Aim 1) using immunoassays and patient blood and autopsy tissue samples. In Aim 2, we
will utilize an innovative dCas9READ method to identify novel repeat expansion mutations in RAN(+) sALS and
sFTD cases and study the toxic effects of putative disease-causing expansion mutations. Lastly, we will test
the hypothesis that decreasing RAN translation using AAV-PKR(K296R) or metformin will improve disease
phenotypes in patient derived induced models and mouse models of sALS, sFTD and SBMA (Aim 3). Taken
together, these studies will provide critical insights into the molecular mechanisms of sALS, sFTD and SBMA
and facilitate the development of unifying ther...

## Key facts

- **NIH application ID:** 10420041
- **Project number:** 1RF1NS126536-01
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Lien Nguyen
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,930,065
- **Award type:** 1
- **Project period:** 2022-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10420041

## Citation

> US National Institutes of Health, RePORTER application 10420041, Novel repeat associated non-AUG (RAN) proteins in sALS, sFTD and SBMA: shared pathological features and unifying therapeutic opportunities (1RF1NS126536-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10420041. Licensed CC0.

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