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This ALS Awareness Month, the ALS Canada Research Program team has summarized what we believe are the most significant research discoveries. This is our second installment for 2018 – for more information see past updates from August 2017, November 2017 and February 2018.
New insights into how mutations in the protein FUS leads to the development of ALS
Mutations in the protein FUS have been linked to ALS. In a healthy cell, FUS can be found in one of three states: (1) as a single protein molecule, (2) grouped together in a liquid droplet state (like a drop of oil in water) or (3) grouped together in a dense gel state (like jelly). In order for FUS to be able to complete one of its intended functions within cells, it must easily be able to switch back and forth between the liquid and gel states. This process, which is referred to as phase separation, appears to be disrupted in ALS. Scientists found that mutations in FUS cause the protein to become trapped in the gel state which is damaging to neuronal cells and over time can lead to cell death. Researchers knew that in order to be able to prevent FUS from becoming trapped in the gel state they needed to better understand the factors that control the liquid to gel transition in cells. Remarkably, four papers published in the April 19 Issue of Cell, a prominent peer-reviewed scientific journal, made significant advances in this understanding. Researchers from all four laboratories were investigating different aspects of FUS and independently reached the same findings, highlighting two specific cellular pathways that control FUS phase separation and may be able to prevent neurodegeneration. One of these studies was funded in part by the Ice Bucket Challenge and the ALS Society of Canada’s partnership with Brain Canada. Together, these findings open up new avenues to explore when developing treatments for FUS-linked ALS, and are of broad importance as these biological mechanisms are part of our evolving understanding of other forms of ALS as well as frontotemporal dementia (FTD).
A promising lead for treatment of an inherited form of ALS
A team of researchers at the University of Liverpool has identified a possible new treatment strategy for an inherited form of ALS. Mutations in the SOD1 protein represent the second most common cause of inherited ALS. It is thought that mutations cause the protein to fold into the wrong 3D shape, a process referred to as misfolding, which then causes it to gain a toxic function. In study findings published in April 2018, researchers set out to identify a drug that may be able to prevent the misfolding of SOD1 and restore its normal function in human cells. After testing a variety of different compounds the researchers found that one, called ebselen, had a positive effect. Ebselen has previously been tested for the treatment of multiple disorders, including stroke, bipolar disorder, and hemorrhage. Since this study was only conducted using human cells outside the body, the results are preliminary but suggest to researchers that ebselen should be further tested in ALS animal models to confirm the positive effect. Ebselen represents one of many unique treatment options being explored for SOD1-linked ALS. As the first genetic mutation discovered for ALS, SOD1 has been studied for more than two decades. In the near future we hope to see a similar number of treatment options in development for all forms of ALS.
What we can learn from extremely rare ALS reversal cases
In extremely rare cases, a person diagnosed with ALS may stop progressing and regain motor function. These cases are referred to as “ALS reversals” and while highly uncommon, they are important to study because they can help researchers to identify genetic differences that may make a person more resistant to ALS and even lead to the development of an effective treatment. This was the case for HIV where the study of a rare group of HIV resistant “elite controllers” led to development of a successful drug treatment. In an April 2018 study, researchers compared the demographics, disease characteristics and self-administered alternative treatments of verified reversal cases to those of patients with typical progressive ALS. The researchers found that people who experienced ALS reversals were more likely to be male, have limb onset disease, and initially progress faster. The results of the study indicated that there are differences that should be further explored between people who experienced ALS reversals compared to typical progressive cases. Despite the limited number of cases to work with, researchers hope continued study will help to identify the mechanism of disease resistance in reversal cases so that it can one day be applied to the vast majority of people who show typical progressive ALS.
Researchers identify a new link between two cellular processes disrupted in ALS
In recent years, researchers have made significant progress in identifying the various cellular pathways that are disrupted in ALS. This is important because a better understanding of the pathways involved, as well as how they interact with each other to cause ALS, is crucial to developing an effective treatment. Two important cellular pathways previously shown to be affected in ALS are (1) stress granule formation and (2) nucleocytoplasmic trafficking. Stress granules are structures that form temporarily when a cell is stressed (i.e. exposed to heat, cold or radiation) to protect important cellular components. Stress granules are only meant to form temporarily; however, in ALS cellular components can become trapped in these structures preventing them from completing their normal functions. Nucleocytoplasmic trafficking, on the other hand, involves the transport of cellular components between two important compartments of the cell and is crucial to cell survival. In a May 2018 study, researchers identified a link between these two pathways. The researchers found that many of the cellular elements that become trapped in stress granules play an important role in the trafficking process. When these cellular elements are trapped in stress granules, trafficking is stalled. Based on these results, researchers are optimistic that if they can regulate stress granule formation within cells they may also be able to restore nucleocytoplasmic trafficking. In fact, gene therapy techniques to reduce stress granule formation are currently being explored as a potential treatment option for ALS.
Advances in models used to study the biology of ALS
In its early stages, medical research is often conducted using disease models (ranging from nerve cells in a dish, to worms, to mice). The use of disease models allows researchers to study the biology of the disease in ways they could not in people. In order to be useful, however, these models must accurately represent how the disease develops in the human body. In an April 2018 study, researchers described a new technique that allowed them to grow a patient’s own neurons and blood vessels together outside the body for the first time. Using what is referred to as “Organ-Chip” technology, the researchers were able to grow spinal motor neurons from stem cells in a more life-like environment than previously possible in petri dishes. This research allows scientists to mimic important parts of the human nervous system and is part of a bigger collaboration that aims to use this technique to advance personalized medicine, a new medical approach to determine the most effective treatment for a person based on their unique biology. Since ALS is causes by many different gene mutations, researchers are hopeful that by creating a living model of the disease with a patient’s own cells they may be able to better predict which treatment option would be most beneficial to that patient and avoid the risk of giving a drug that may be costly and ineffective. Organ-Chip technology is not specific to the study of ALS, but rather can be applied to a variety of different conditions including Parkinson’s and Crohn’s disease, and so is an important new tool for the medical community as a whole.
