# Role of C9orf72 in Neurodegeneration

> **NIH NIH R01** · CEDARS-SINAI MEDICAL CENTER · 2020 · $382,813

## Abstract

Project Summary
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are disorders with
overlapping clinical presentation, genetics, and pathology. Large expansions of a GGGGCC
hexanucleotide repeat in the first intron/promoter of the C9orf72 gene are the most commonly
identified genetic cause of familial and sporadic ALS and FTD (C9-ALS/FTD), and recently
C9orf72 repeat expansions were reported in other neurodegenerative diseases including
Alzheimer's disease.It remains uncertain whether the repeat expansion in C9orf72 causes
neurodegeneration primarily through a toxic gain of function, loss of function, or both. In our
preliminary data we found that contrary to current dogma, C9orf72 expression is higher in
microglia than in neurons, and that the primary defects in C9orf72 deficient mice are due to
altered myeloid cell function in both the spleen and the brain. Our goal in this project is to test
the hypothesis that decreased levels of C9orf72 caused by the repeat expansion lead to altered
microglial function, which acts in concert with gain of function manifestations in neurons (RNA
foci, RAN dipeptides) to drive neurodegeneration in C9-ALS/FTD. We propose to i) define the
molecular defects in C9orf72 deficiency macrophages and microglia, ii) determine whether
peripheral blood macrophages from C9orf72 patients show similar alterations, and iii) cross the
C9orf72 deficient mice to a novel BAC transgenic C9orf72 model to test the idea that C9orf72
deficiency contributes to the pathogenesis of C9-ALS/FTD.

## Key facts

- **NIH application ID:** 9934307
- **Project number:** 5R01NS097545-05
- **Recipient organization:** CEDARS-SINAI MEDICAL CENTER
- **Principal Investigator:** Robert Baloh
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $382,813
- **Award type:** 5
- **Project period:** 2016-07-01 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9934307

## Citation

> US National Institutes of Health, RePORTER application 9934307, Role of C9orf72 in Neurodegeneration (5R01NS097545-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9934307. Licensed CC0.

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