Stormy sea with RNA strand-shaped clouds and a distant lighthouse, symbolizing the complexities and potential therapies for C9orf72-related ALS/FTD.

C9orf72: Unraveling the Perfect Storm Behind ALS and Frontotemporal Dementia

Reese Marlowe in Health & Wellness June 2025 • 7 min read.

"Decoding the Role of Non-Coding RNA in Neurodegenerative Diseases"

Amyotrophic Lateral Sclerosis (ALS), also recognized as motor neuron disease (MND), is a relentless and progressive neurodegenerative condition affecting motor neurons. Typically emerging in late adulthood, with onset peaking between ages 50 and 75, ALS presents a grim prognosis, averaging survival of only three to five years post-diagnosis. While approximately 5% of ALS cases are familial, demonstrating an autosomal dominant pattern of inheritance, this is often compounded by incomplete penetrance among affected families.

Adding another layer of complexity, the phenotypic spectrum extends beyond ALS. Frontotemporal dementia (FTD) is diagnosed in 5-15% of ALS patients, while up to half experience FTD-like symptoms. FTD, characterized by frontal and temporal lobe atrophy, leads to cognitive-behavioral changes, including disinhibition, apathy, personality alterations, and language disturbances. Conversely, around 12.5% of FTD patients also develop ALS, and up to 40% exhibit features of both conditions. Mirroring ALS, at least 10% of FTD cases demonstrate autosomal dominant inheritance, with familial history reported in up to 40% of cases. This convergence highlights ALS and FTD as spectrum disorders, stemming from mutations in shared genes, leading to varied clinical presentations, even within the same family.

Despite their distinct clinical manifestations, ALS and FTD share key pathological characteristics, including TDP-43 proteinopathy in most ALS and many FTD cases. Recent evidence suggests a prion-like spread of pathology through the central nervous system (CNS) in both conditions. In ALS, pathology spreads via contiguous cell-to-cell mechanisms and network propagation along synaptic pathways, correlating with the progression from focal to generalized clinical signs and symptoms. Similarly, FTD shows pathological spread within the brain. Thus, the clinical presentation within the ALS/FTD spectrum depends on the initial affected brain or spinal cord region, with progression tied to subsequent pathological spread.

Unmasking C9orf72: How Does RNA Dysfunction Drive ALS/FTD?

Stormy sea with RNA strand-shaped clouds and a distant lighthouse, symbolizing the complexities and potential therapies for C9orf72-related ALS/FTD.

Since the 2011 discovery of the C9orf72 gene, it has become clear that there is significant variability in the phenotypes associated with this mutation, and that modifying mutations and variants in other ALS/FTD-related genes are often present in affected expansion-positive patients. The underlying pathogenetic mechanism of the C9orf72 expansion (and indeed that of all ALS/FTD) remains the subject of intense ongoing research across the globe. However, a number of common themes have emerged in relation to neurodegenerative diseases in general and to ALS/FTD in particular. Principal among these is the seemingly central role of RNA in disease, whether it be abnormal pre-mRNA splicing, abnormal RNA transport, microRNA dysregulation, repeat-associated non-ATG-dependent (RAN) translation or the sequestration of important cellular factors by toxic non-coding RNA.

The function of the C9orf72 protein has yet to be fully elucidated. Bioinformatic and experimental evidence supports a role for it in vesicular trafficking as a Rab-GTPase exchange factor (Rab-GEF) and indeed an interaction with Rab proteins has been demonstrated, as well as the protein showing a regulatory effect on autophagy and extracellular vesicle release. C9orf72 protein has also been shown to be necessary for the formation of stress granules, suggesting that reduced expression could impact upon stress response. The gene has orthologues in organisms as divergent as C. elegans, suggesting a key conserved role in multicellular animals, although no such orthologue appears to exist in Drosophila melanogaster.

Abnormal Pre-mRNA Splicing: Disruptions in the normal process of splicing pre-mRNA can lead to the production of faulty or non-functional proteins, contributing to the pathology of ALS/FTD.
Abnormal RNA Transport: Proper transport of RNA molecules is essential for protein synthesis. When this process is disrupted, it can lead to a deficit of necessary proteins in the areas where they are most needed.
MicroRNA Dysregulation: MicroRNAs (miRNAs) are small RNA molecules that regulate gene expression. Dysregulation of miRNAs can affect the expression of multiple genes, further complicating the disease mechanism.
Repeat-Associated Non-ATG-Dependent (RAN) Translation: This unusual form of translation can produce toxic proteins from repetitive sequences in the RNA, contributing to neuronal damage.
Sequestration of Cellular Factors: Toxic non-coding RNA can bind to and sequester important cellular factors, disrupting their normal function and leading to cellular dysfunction.

Thus, the current consensus is that while C9orf72 loss of function may play an important role in the disease, and although a decrease in gene expression has been seen in the brain in the presence of the expansion, the loss-of-function mechanism on its own is not the sole pathogenic driver of the condition. The GC-rich nature of the C9orf72 repeat and its similarity to the (CGG)n repeat found in fragile X syndrome led to the suspicion that large expansions might induce DNA hypermethylation at the gene's locus. Indeed, it has been known for many years that a rare folate-sensitive chromosome fragile site exists at the 9p21 locus, the same genomic region as the C9orf72 locus.

Navigating the Future: Potential Therapeutic Strategies

The story of C9orf72 has been a case of the gene confounding those studying it at every turn. Firstly, the repeat expansion itself is hard to model owing to its large size, G-C content and inherent instability. Secondly, the disease it causes (ALS/FTD) is only partially understood in terms of its aetiology and therefore it is hard to interpret the contribution of the expansion to disease pathogenesis. Furthermore, the behaviour of the repeat expansion and its clinical effects do not appear to conform to what we have learnt from other repeat expansion disorders, either in terms of genetic anticipation or in relation to a correlation between expansion size and age of onset. Perhaps most clear of all is that ALS/FTD is not a disease that is caused by any one single factor in isolation. From a non-coding RNA point of view, then, what key questions should be answered in relation to C9orf72? This review helps highlight several potential avenues for further investigation. Firstly, the antisense IncRNA of C9orf72 should be studied in more detail in order to ascertain its natural function and its potential role in controlling C9orf72 expression. This might include consideration of potential secondary miRNA effects as well as possible roles in epigenetic regulation. Secondly, studying the role of hnRNP-H and other specific RBPs in relation to C9orf72 and the effects of their sequestration by the expanded repeat should help elucidate some of the key RNA misprocessing events in this condition. Thirdly, the role of R-loop formation in this disease should be studied in more detail to ascertain its relationship to DNA damage, repeat instability, various RBP deficiencies and the potential for ASO therapeutics.

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Everything You Need To Know

How does the C9orf72 gene mutation contribute to the development of both Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD)?

The C9orf72 gene mutation leads to the production of toxic non-coding RNA, which can cause several RNA dysfunctions. These dysfunctions include abnormal pre-mRNA splicing, abnormal RNA transport, microRNA dysregulation, repeat-associated non-ATG-dependent (RAN) translation, and the sequestration of important cellular factors. These RNA dysfunctions disrupt normal cellular processes, leading to neuronal damage characteristic of both ALS and FTD. While the loss of C9orf72 function may play a role, it's not the sole driver; the GC-rich repeat expansion can also induce DNA hypermethylation, further complicating the disease mechanism. The exact mechanisms of how these factors interact to cause ALS and FTD are still under intense investigation.

What are the key pathological hallmarks shared between ALS and FTD, and how do they contribute to disease progression?

Both Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) share key pathological characteristics, most notably TDP-43 proteinopathy. This means there's an abnormal accumulation and mislocalization of the TDP-43 protein in the brain and spinal cord. Recent evidence also suggests a prion-like spread of pathology through the central nervous system (CNS) in both conditions. In ALS, this spread occurs via cell-to-cell mechanisms and network propagation along synaptic pathways, correlating with the progression from focal to generalized clinical signs. Similarly, in FTD, pathological spread occurs within the brain. The clinical presentation depends on the initial affected brain or spinal cord region, with disease progression linked to subsequent pathological spread.

What role do non-coding RNAs play in the pathology of C9orf72-related ALS and FTD, and what specific dysfunctions are involved?

Non-coding RNAs play a central role in C9orf72-related Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) by contributing to several key dysfunctions. These include: (1) Abnormal pre-mRNA splicing, which leads to faulty proteins; (2) Abnormal RNA transport, causing a deficit of necessary proteins where needed; (3) MicroRNA dysregulation, affecting the expression of multiple genes; (4) Repeat-associated non-ATG-dependent (RAN) translation, producing toxic proteins; and (5) Sequestration of cellular factors, disrupting their normal function. Understanding these specific dysfunctions can lead to potential therapeutic strategies targeting RNA-related mechanisms.

Beyond the C9orf72 mutation, what other genetic factors are implicated in the development of ALS and FTD?

While the C9orf72 gene mutation is a significant factor in both ALS and FTD, modifying mutations and variants in other ALS/FTD-related genes are often present in affected expansion-positive patients. The phenotypic spectrum associated with the C9orf72 mutation is highly variable. This variability suggests that the presence of other genetic mutations can influence the onset and progression of these diseases. Research is ongoing to identify and understand these additional genetic factors, which may include genes involved in RNA processing, protein degradation, and cellular stress response.

What are some potential therapeutic strategies being explored that target the non-coding RNA aspects of C9orf72-related ALS and FTD?

Several therapeutic strategies are being explored to target the non-coding RNA aspects of C9orf72-related Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD). One potential avenue is to study the antisense IncRNA of C9orf72 to understand its function and role in controlling C9orf72 expression, including its potential effects on miRNA and epigenetic regulation. Another approach involves studying the role of hnRNP-H and other specific RBPs in relation to C9orf72 and the effects of their sequestration by the expanded repeat to elucidate key RNA misprocessing events. Additionally, research is focusing on the role of R-loop formation to ascertain its relationship to DNA damage, repeat instability, RBP deficiencies, and the potential for ASO therapeutics. These strategies aim to correct or mitigate the effects of RNA dysfunction, offering promising avenues for future treatments.