A New Clue to One of the Most Common Genetic Causes of ALS and FTD

Scientists have uncovered critical new insights into how a common genetic mutation drives amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two devastating neurodegenerative diseases. The findings, published in Science, help clarify the cause of nerve cells in people with a mutation in the C9ORF72 gene and point toward more precise therapeutic strategies.

Why C9ORF72 Matters

Mutations in the C9ORF72 gene are the most common known genetic cause of ALS and FTD, and can lead to an ALS-FTD spectrum disorder. In people with this mutation, a short sequence of DNA is repeated far more times than normal. Instead of a handful of repeats, cells may contain hundreds or even thousands.

For years, scientists have known that this abnormal repetition disrupts how cells function, but exactly how it causes damage has been a major unanswered question. Understanding that mechanism is essential for designing treatments that address the root cause of disease rather than just symptoms.

Toxic Proteins, Not Just Faulty RNA

Cells containing the C9ORF72 repeat-expansion behave differently from healthy cells. The repeated genetic sequence is copied into RNA, which is then used in an unusual process to make abnormal proteins known as dipeptide repeat proteins, or DPRs.

These proteins accumulate inside neurons and interfere with normal cellular functions. However, researchers have long debated whether the main problem comes from the expanded RNA itself or from the toxic proteins produced from it.

Shown in this publication, researchers were able to separate these two effects. They used advanced genetic tools to block the production of the toxic proteins while leaving the repetitive RNA intact. This allowed them to observe what happens when DPRs are removed from the equation.

When production of the toxic proteins was stopped, neurons survived longer, inflammation was reduced, and key features of ALS and FTD were significantly improved in disease models. This happened even though the abnormal RNA was still present.

These findings suggest that the toxic proteins, the DPRs, are a primary driver of neurodegeneration in C9ORF72-related ALS and FTD.

Why This Discovery Is Important

This research helps resolve a long-standing question in the ALS and FTD field and provides a clearer target for therapy development. Rather than needing to eliminate the expanded RNA entirely, treatments could focus on preventing the production of harmful proteins.

That distinction matters. Targeting a specific disease mechanism increases the likelihood of developing therapies that are both effective and precise, while minimizing unintended effects on healthy cells.

The Role of Target ALS

This work was supported in part by Target ALS, whose mission is to break down barriers that slow ALS research and accelerate the path to effective treatments. Target ALS invests in early-stage research that allows scientists to ask foundational questions about disease biology, long before discoveries reach this level of clarity.

A core part of that approach is providing no-strings-attached access to Target ALS Research Cores, scientific resources that are available to researchers worldwide. These cores give scientists access to rigorously characterized tools, models, and datasets that are often difficult, expensive, or time-consuming to generate independently.

By removing intellectual property restrictions and administrative barriers, Target ALS enables researchers to move faster, collaborate more freely, and focus on discovery rather than cutting through red tape. This model is especially impactful in ALS research, where fragmented resources and duplication of effort have historically slowed progress.

In the case of C9ORF72-related ALS and FTD, early investment and open access to specialized reagents helped lay the groundwork for the mechanistic insights reported in this study. By supporting research at its earliest stages and ensuring that critical tools are shared rather than siloed, Target ALS helps discoveries advance from fundamental biology toward therapeutic strategies that are informed by a clear understanding of disease mechanisms.

As Dr. Clotilde Lagier-Tourenne, a leader on the research team, shared:

“Over the years, Target ALS has provided exceptional support through programs dedicated to elucidating C9ORF72 ALS/FTD mechanisms and by enabling access to unique reagents. Continued efforts to advance our understanding of this complex disease are crucial for the development of mechanism-informed therapeutic strategies.”

Looking Ahead

While much work remains before these discoveries translate into treatments for people living with ALS or FTD, this study represents an important step forward. By identifying what is truly driving damage inside neurons, researchers can now focus on designing therapies that directly interrupt that process.
Progress like this depends on sustained investment. Donations to Target ALS help fund early-stage research, expand access to shared research resources, and keep promising discoveries moving forward. Support today helps ensure that scientists can continue cutting through barriers and accelerating progress toward effective treatments for ALS.

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