# Molecular Characterization of ALS/FTD in a novel C9orf72 BAC mouse model.

> **NIH NIH R01** · UNIVERSITY OF FLORIDA · 2020 · $695,423

## Abstract

Project Summary
The expansion of a microsatellite GGGGCC repeat in the C9orf72 gene has been linked to both familial and
sporadic forms of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). While the molecular
basis of this disease (C9-ALS/FTD) remains largely unknown, proposed disease mechanisms include C9orf72
loss of function due to haploinsufficiency, RNA gain of function (GOF) leading to protein sequestration and
repeat-associated non-ATG (RAN) translation resulting in the production of toxic C9-RAN dipeptide repeat
proteins. Based on our prior studies on other microsatellite expansion diseases, this proposal is designed to
test our sequestration failure hypothesis, which integrates RNA and RAN gain of function mechanisms.
According to this hypothesis, bidirectional sense and antisense C9orf72 transcription results in the recruitment
of cellular factors to repeat expansion RNAs to produce sense and antisense RNA foci that sequester these
toxic RNAs in the nucleus. Somatic repeat expansion and/or age-related cellular stress results in titration of
GGGGCC and GGCCCC RNA binding proteins followed by nucleocytoplasmic export of these RNAs and
translation of highly toxic C9-RAN proteins in the cytoplasm that lead to neurodegeneration. We have
generated a BAC transgenic model of C9-ALS/FTD that will allow us to test this hypothesis. This mouse
develops both the molecular (RNA foci, C9-RAN proteins) and pathophysiological (neuronal loss, paralysis,
decreased survival) features of C9-ALS/FTD. In this proposal, we will initially test the hypothesis that RNA
GOF effects precede RAN protein accumulation by performing RNA-FISH, transcriptome analysis and
immunological assays at various developmental periods and in different brain and spinal cord regions on
asymptomatic, pre-symptomatic and symptomatic C9-BAC mice. This information will be used in conjunction
with histopathological and electrophysiological assays test the hypothesis that C9-RAN protein accumulation
triggers neurodegeneration and the acute disease phase. The possibility that stress pathways modulate RAN
translation will also be tested. Finally, we will test whether antisense oligonucleotide (ASO) gapmer-mediated
knockdowns of sense, antisense or both sense and antisense C9orf72 transcripts blocks the development of
RNA and RNA toxicity in our C9-BAC transgenic mice. Overall, the objective of this study is to define
pathogenic mechanisms underlying C9-ALS/FTD disease development and progression and provide an
accessible and well-characterized mouse model for therapeutic development.

## Key facts

- **NIH application ID:** 9947751
- **Project number:** 5R01NS098819-05
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Laura P.W Ranum
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $695,423
- **Award type:** 5
- **Project period:** 2016-08-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9947751

## Citation

> US National Institutes of Health, RePORTER application 9947751, Molecular Characterization of ALS/FTD in a novel C9orf72 BAC mouse model. (5R01NS098819-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9947751. Licensed CC0.

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