# Cell-type-specific toxicity of C9orf72 repeat expansions in FTD and ALS

> **NIH NIH R01** · EMORY UNIVERSITY · 2024 · $390,000

## Abstract

PROJECT SUMMARY/ABSTRACT
 Expanded GGGGCC hexanucleotide repeats in the C9orf72 gene were recently identified as the most
common genetic cause of Frontotemporal Dementia (FTD) and Amyotrophic Lateral Sclerosis (ALS), two
neurodegenerative disorders with clinical, pathological and genetic overlaps. Proposed disease mechanisms
include loss of C9orf72 protein function and gain of toxicity from the bidirectionally transcribed sense or
antisense repeat-containing RNAs, mediated by sequestration of RNA binding proteins into RNA foci or by
production of at least five different aberrant dipeptide repeat (DPR) proteins [GA, GP, GR, PR, and PA] from
the intronic sequence through a nonconventional translation mechanism called repeat-associated non-AUG-
dependent (RAN) translation. Several studies demonstrated that gain of toxicity from C9orf72 repeat containing
RNAs plays a central role in disease pathogenesis. It is yet unknown which specific cell types in the central
nervous system is responsible for the disease pathogenesis from gain of toxicity. C9orf72 loss of function
alone is insufficient to cause FTD/ALS in mice, but our preliminary data showed it exacerbates diseases
together with gain of toxicity. C9orf72 plays an important role in the immune cells as C9orf72 null mice develop
splenomegaly and enlarged cervical lymph nodes. However, the function of C9orf72 in microglia and its
contribution to FTD/ALS is not determined. In this proposal, will determine 1) molecular pathways altered by
C9orf72 loss of function in microglia using genome-wide RNA sequencing and whether such changes in
microglia will lead to neuronal toxicity (Aim 1); 2) Whether C9orf72 loss of function in microglia contributes to
FTD/ALS pathogenesis caused by gain of toxicity from the repeat containing RNAs in mice (Aim 2); and 3)
cell-type-specific toxicity from C9orf72 repeat containing RNAs (Aim 3). If successful, the proposed study will
further help us understand the disease mechanisms of C9orf72 repeat expansions in FTD and ALS and
identify potential therapeutic interventions.

## Key facts

- **NIH application ID:** 10841522
- **Project number:** 5R01AG068247-05
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Jie Jiang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $390,000
- **Award type:** 5
- **Project period:** 2020-09-15 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10841522

## Citation

> US National Institutes of Health, RePORTER application 10841522, Cell-type-specific toxicity of C9orf72 repeat expansions in FTD and ALS (5R01AG068247-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10841522. Licensed CC0.

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