Critical link between protein and ALS disease offers new hope

Scientists are uncovering new insights into the mechanisms driving neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). These fatal diseases are linked to mutations in the C9orf72 gene, the most common genetic cause of ALS and FTD.

This mutation generates toxic dipeptide repeats (DPRs), specifically poly-PR and poly-GR, which wreak havoc on cells. Understanding how these DPRs affect cellular structures is a crucial step toward developing effective therapies.

In healthy cells, specific molecules can spontaneously organize into liquid-like compartments called membrane-less organelles. Unlike traditional organelles enclosed by membranes, these structures form through liquid–liquid phase separation (LLPS), similar to how oil separates from water. These compartments play vital roles in cellular functions, from regulating genes to managing stress responses.

Stress granules, a type of membrane-less organelle, are temporary structures that form when cells are under stress, such as during viral infections. They act as molecular sanctuaries, protecting vital proteins and RNAs until the stress subsides. At the center of this process is G3BP1, a protein essential for stress granule formation.

When stress occurs, G3BP1 transitions from a closed, inactive state to an open, active state, enabling stress granules to form and protect the cell.

However, the toxic DPRs produced in C9-ALS and FTD disrupt this process. These DPRs bind to G3BP1 far more strongly than the RNA molecules that usually activate it. This excessive binding forces G3BP1 into overdrive, triggering the formation of stress granules inappropriately or preventing their proper disassembly.

Over time, these stress granules become less dynamic, forming harmful aggregates that impair cellular function. This phenomenon is a hallmark of neurodegenerative diseases.

Margot Van Nerom, a researcher from Structural Biology Brussels, explains, “In a specific form of ALS, called C9-ALS, toxic dipeptide repeats bind strongly to G3BP1, disrupting its normal function and stress granule formation. These improperly broken-down granules form aggregates, damaging cells.”

This disruption has profound implications for cellular health. Membrane-less organelles rely on their dynamic liquid-like properties to carry out essential functions. When stress granules become rigid and aggregate, they lose their ability to protect the cell. This failure contributes to the degeneration of neurons, a defining characteristic of ALS and FTD.

Further investigation into the molecular interactions between DPRs and G3BP1 revealed a key mechanism underlying this toxicity. G3BP1 contains multiple regions, including intrinsically disordered regions (IDRs), which lack a fixed structure but are critical for its function.

One of these regions, IDR1, is highly negatively charged and interacts with the positively charged IDR3 region to keep the protein in an inactive state. RNA binding to IDR3 opens G3BP1, allowing stress granules to form.

Toxic DPRs, however, mimic RNA in their ability to bind G3BP1, but their effect is far more potent. They bind to the negatively charged IDR1 with extraordinary strength, over a thousand times stronger than RNA.

This unnatural interaction forces G3BP1 into a hyperactive state, promoting stress granule formation even in the absence of stress. Moreover, these toxic interactions lead to the transition of stress granules into rigid, aggregated states, further amplifying cellular dysfunction.

Van Nerom emphasizes the broader significance of these findings: “Our research highlights how toxic DPRs affect not only stress granules but also other membrane-less organelles like nucleoli. These discoveries pave the way for new therapeutic interventions.”

The implications of this research extend beyond stress granules. The same toxic DPRs also disrupt the functioning of nucleoli, another type of membrane-less organelle within the nucleus. Nucleoli are critical for producing ribosomes, the cell’s protein factories. Like stress granules, nucleoli rely on LLPS for their formation and function.

The DPRs interfere with nucleoli by binding to nucleophosmin 1 (NPM1), a key driver of nucleolar phase separation. This disruption further underscores the wide-ranging impact of DPR toxicity on cellular health.

Researchers are now drawing parallels between the effects of toxic DPRs on different organelles. Both stress granules and nucleoli rely on proteins with similar structural properties, such as G3BP1 and NPM1, to drive phase separation. By binding to these proteins, DPRs disrupt their normal functioning, leading to cellular damage. This shared mechanism suggests a unifying explanation for the toxicity observed in ALS and FTD.

The concept of "condensatopathies" is emerging to describe diseases caused by the malfunction of membrane-less organelles. The ability of these structures to form and dissolve dynamically is essential for cellular health. When this process is disrupted, the resulting aggregates can lead to a wide range of diseases, including cancer, viral infections, and neurodegeneration.

Van Nerom’s findings were based on studies of isolated proteins, but the research team plans to extend their work to animal models and clinical trials. “This is an important step forward in understanding the role of dipeptide repeats in ALS and other neurodegenerative disorders,” she states. “These discoveries are laying the groundwork for the development of new treatments.”

Understanding the molecular mechanisms driving DPR toxicity not only sheds light on ALS and FTD but also opens the door to potential therapeutic strategies.

By targeting the interactions between toxic DPRs and proteins like G3BP1 or NPM1, scientists hope to restore the dynamic properties of membrane-less organelles. Such interventions could prevent the formation of harmful aggregates and protect neurons from degeneration.

This research underscores the importance of basic science in unraveling complex diseases. By examining the intricate details of cellular processes, scientists are making strides toward solving some of the most challenging problems in medicine.

For individuals and families affected by ALS and FTD, these discoveries offer a glimmer of hope for the future.

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