# Molecular Basis of Pathogenic Cascades in ALS/FTD Initiated from C9orf72 Hexanucleotide Repeat Expansion

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2024 · $612,820

## Abstract

Project Summary
 Nucleotide repeat elements, including microsatellites or short tandem repeats, are
common in eukaryotic genomes. Expansions of short nucleotide repeats have been linked to
over 50 different types of genetic disorders, primarily neurological and neuromuscular disorders.
Our understanding of how these repeat elements in the human genome cause diseases is still
in its infancy. A hexanucleotide repeat expansion in a noncoding region of the C9orf72 gene has
been linked to the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and
frontotemporal dementia (FTD). ALS is characterized by loss of motor neurons, and the C9orf72
hexanucleotide repeat expansion represents the most common genetic cause of both familial
and sporadic ALS. FTD is characterized by degeneration of the frontal and temporal lobes of the
brain and is the second-most common type of dementia in people older than 65; the C9orf72
hexanucleotide repeat expansion is also the most common genetic cause of FTD. This repeat
expansion is also found to contribute to Alzheimer’s disease and Huntington’s disease. To help
relieve the public health burden associated with these diseases, it is important to understand the
mechanisms underlying their pathogenesis. Multiple hypotheses exist to explain the pathogenic
mechanisms underlying C9orf72-linked ALS/FTD. The goal of the proposed project is to
elucidate novel mechanisms through which the C9orf72 hexanucleotide repeat expansion leads
to molecular defects and neuronal toxicity, focusing on gain-of-function mechanisms. The
specific aims are to identify previously unknown pathogenic cascades initiated by the C9orf72
hexanucleotide repeat expansion. These novel pathogenic cascades include, but are not limited
to, RNA toxicity and non-canonical translation products resulting from the C9orf72
hexanucleotide repeat expansion. We propose a series of fundamental studies that combine
biochemical, molecular, and genetic approaches to shed light on the novel pathways leading to
ALS/FTD pathogenesis and to identify potential intervention strategies. Successful completion
of the project is expected to provide insights into fundamental mechanisms of
neurodegeneration in ALS/FTD that may ultimately lead to novel approaches for treating
ALS/FTD and other relevant neurodegenerative diseases.

## Key facts

- **NIH application ID:** 10840945
- **Project number:** 5R01NS128494-03
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Jiou Wang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $612,820
- **Award type:** 5
- **Project period:** 2022-07-15 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10840945

## Citation

> US National Institutes of Health, RePORTER application 10840945, Molecular Basis of Pathogenic Cascades in ALS/FTD Initiated from C9orf72 Hexanucleotide Repeat Expansion (5R01NS128494-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10840945. Licensed CC0.

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