Surreal brain with RNA strands, symbolizing ALS/FTD complexity.

Decoding the Perfect Storm: How RNA Dysfunction Leads to ALS and Frontotemporal Dementia

Jordan Keane in Health & Wellness June 2025 • 4 min read.

"New research illuminates the critical role of non-coding RNA in C9orf72-related ALS and FTD, offering potential targets for future therapies."

Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND), is a devastating neurodegenerative condition that progressively destroys motor neurons. Typically striking in late adulthood, between the ages of 50 and 75, ALS is characterized by rapid progression, with an average survival of only three to five years post-diagnosis. While about 5% of cases are familial, showing an autosomal dominant inheritance pattern, incomplete penetrance and variable phenotypic expression complicate the genetic landscape.

Adding another layer of complexity, a significant percentage of ALS patients also exhibit symptoms of frontotemporal dementia (FTD), with estimates ranging from 5-15% receiving a formal FTD diagnosis and up to 50% displaying FTD-like symptoms. FTD, characterized by frontal and temporal lobe atrophy, results in behavioral changes like disinhibition, apathy, personality shifts, and language difficulties. A portion of FTD patients, around 12.5%, also develop ALS, highlighting the intertwined nature of these conditions.

Both ALS and FTD share key pathological features, including TDP-43 proteinopathy, where the TDP-43 protein mislocalizes and aggregates within cells. This mislocalization and aggregation contributes to a prion-like spread of the disease within the central nervous system (CNS), moving from focal points to more generalized clinical manifestations. Unraveling the genetic and molecular underpinnings of ALS and FTD is crucial for developing effective therapies, and understanding the role of RNA is emerging as a central theme.

The C9orf72 Gene: A Perfect Storm of Dysfunction

Surreal brain with RNA strands, symbolizing ALS/FTD complexity.

The discovery of a hexanucleotide repeat expansion in the C9orf72 gene has revolutionized our understanding of ALS and FTD. This expansion, located in a non-coding region of the gene, is the most common genetic cause of both diseases. The repeat expansion leads to a complex cascade of cellular events:

RNA Toxicity: The transcribed repeat expansion creates toxic RNA molecules that can disrupt normal cellular processes.

RNA Foci: These molecules form clumps within the nucleus, sequestering important RNA-binding proteins.
Dipeptide Repeats: The repeat expansion can be translated into toxic dipeptide repeat proteins through a non-traditional form of translation.
R-loop Formation: The repeat expansion can lead to the formation of R-loops, which are structures where RNA binds to DNA, disrupting normal DNA processes.

Epigenetic Modifications: The C9orf72 expansion also affects the epigenetic landscape of the gene, leading to reduced expression. This complex interplay of factors contributes to the neurodegenerative processes observed in ALS and FTD.

Navigating Towards Future Therapies

While the complexity of C9orf72-related ALS/FTD presents significant challenges, it also offers hope for future therapeutic interventions. By targeting specific aspects of the disease process—such as reducing RNA toxicity, preventing R-loop formation, or modulating epigenetic modifications—researchers aim to develop effective treatments for these devastating conditions. The ongoing exploration of RNA's role in neurodegeneration holds promise for improving the lives of those affected by ALS and FTD.

About this Article -

This article was crafted using a human-AI hybrid and collaborative approach. AI assisted our team with initial drafting, research insights, identifying key questions, and image generation. Our human editors guided topic selection, defined the angle, structured the content, ensured factual accuracy and relevance, refined the tone, and conducted thorough editing to deliver helpful, high-quality information.See our About page for more information.

This article is based on research published under:

DOI-LINK: 10.1016/j.ncrna.2018.09.001, Alternate LINK

Title: Non-Coding Rna In C9Orf72-Related Amyotrophic Lateral Sclerosis And Frontotemporal Dementia: A Perfect Storm Of Dysfunction

Subject: Biochemistry (medical)

Journal: Non-coding RNA Research

Publisher: Elsevier BV

Authors: Andrew G.L. Douglas

Published: 2018-12-01

Everything You Need To Know

What is the role of the C9orf72 gene in ALS and frontotemporal dementia (FTD)?

The C9orf72 gene is significant because a hexanucleotide repeat expansion within its non-coding region is the most common genetic cause of both ALS and FTD. This expansion leads to several toxic effects, including RNA toxicity, the production of toxic dipeptide repeat proteins, and epigenetic modifications that reduce gene expression. These factors collectively contribute to the neurodegenerative processes observed in ALS and FTD. Further research into the mechanisms related to the C9orf72 gene may provide insights into other genes and therapeutic treatments.

How does RNA toxicity contribute to the development of ALS and FTD in the context of C9orf72 expansions?

In C9orf72-related ALS and FTD, the transcribed repeat expansion creates toxic RNA molecules. These molecules form clumps known as RNA foci within the cell nucleus, which then sequester RNA-binding proteins, disrupting normal cellular processes. Also, the repeat expansion can result in R-loop formation, where RNA binds to DNA, further disrupting normal DNA processes. Reducing RNA toxicity is seen as a therapeutic target.

What is TDP-43 proteinopathy and why is it significant in understanding ALS and FTD?

TDP-43 proteinopathy refers to the mislocalization and aggregation of the TDP-43 protein within cells. This is a key pathological feature shared by both ALS and FTD. When TDP-43 mislocalizes, it contributes to a prion-like spread of the disease within the central nervous system (CNS), moving from specific points to more widespread clinical manifestations. Understanding TDP-43 proteinopathy is crucial for developing effective therapies that can prevent or reverse this protein mislocalization and aggregation.

What are dipeptide repeat proteins, and how are they related to C9orf72-associated ALS and FTD?

Dipeptide repeat proteins are toxic proteins produced through a non-traditional form of translation from the C9orf72 repeat expansion. The hexanucleotide repeat expansion in the C9orf72 gene is translated into these proteins, contributing to the pathology of both ALS and FTD. These proteins disrupt normal cellular functions, and reducing their production is a potential therapeutic strategy. This unusual translation mechanism highlights the complexity of the genetic defects that lead to neurodegeneration.

What therapeutic strategies are being considered to combat ALS and FTD related to C9orf72 gene?

Several therapeutic strategies are under consideration to address C9orf72-related ALS and FTD. These include reducing RNA toxicity, preventing R-loop formation, and modulating epigenetic modifications. RNA toxicity reduction aims to prevent the formation of toxic RNA molecules and their subsequent sequestration of RNA-binding proteins. Preventing R-loop formation focuses on stabilizing DNA and ensuring proper DNA processing. Modulating epigenetic modifications seeks to restore normal gene expression. Addressing each of these key disease pathways could lead to more effective treatments for these devastating conditions.