# Exploring Mechanisms of Pathogenicity in C9ORF72 Frontotemporal Dementia and Amyotrophic Lateral Sclerosis

> **NIH NIH R00** · CASE WESTERN RESERVE UNIVERSITY · 2021 · $248,999

## Abstract

Project Summary/Abstract
Age-related neurodegenerative disorders represent a major financial and emotional burden to society, but to date no
preventative strategies have been developed. Frontotemporal dementia (FTD) and Amyotrophic lateral sclerosis (ALS) are
relentlessly progressive diseases which involve the degeneration of neurons important for behavior and muscle movement,
respectively. A hexanucleotide repeat expansion in a non-protein-coding region of the gene C9ORF72 was recently
discovered to be the most common cause of FTD and ALS, responsible for 10% of all diagnoses. Two prevailing
hypotheses have been suggested to explain how this mutation leads to progressive loss of neurons. The gain of function
(GOF) hypothesis proposes that toxic molecules produced from the repeat expansion disrupt neural function and lead to
their destruction. The loss of function (LOF) hypothesis proposes that the C9ORF72 protein plays an important role in
support of neural function and survival and that reduced expression of this gene directly or indirectly sensitizes neurons to
disease. New evidence indicates that the mouse ortholog of C9ORF72 functions in the immune system to limit
inflammation and autoimmunity, although the exact mechanisms require further study. The first AIM of this proposal will
be to identify pathways and cell types that contribute to inflammation when the C9ORF72 ortholog is reduced and to
determine whether induced pluripotent stem cell-derived microglia-like cells from humans with the C9ORF72 repeat
expansion display similar inflammatory phenotypes. The second AIM of this proposal seeks to test the validity of the
LOF hypothesis in live organisms by injecting virus containing the hexanucleotide repeat expansion into mice that express
normal or reduced levels of the C9ORF72 ortholog. If lower levels of the C9ORF72 ortholog sensitize animals to toxic
features of the repeat expansion, this would provide support for developing therapies aimed at boosting levels of
C9ORF72 or inhibiting pathways affected by its reduction. The candidate will train with experts in diverse fields to
develop the technical skills necessary to complete these AIMs and to identify disease relevant pathways which can be
pursued in the independent phase of this proposal. Continued training with the candidate’s advisor and expert
collaborators will prepare him to succeed in his goal to run an independent research group in which he mentors
investigators of all levels and pursues hypotheses aimed at understanding etiologies of neurodegenerative disease.

## Key facts

- **NIH application ID:** 10382565
- **Project number:** 4R00AG057808-03
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Aaron Burberry
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $248,999
- **Award type:** 4N
- **Project period:** 2021-07-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10382565

## Citation

> US National Institutes of Health, RePORTER application 10382565, Exploring Mechanisms of Pathogenicity in C9ORF72 Frontotemporal Dementia and Amyotrophic Lateral Sclerosis (4R00AG057808-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10382565. Licensed CC0.

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