ALS researchers from around the world continue to build upon existing work and make new discoveries in the hopes of realizing a future without ALS. In the October 2023 Research Update, you’ll learn about advances in understanding the presymptomatic stage of ALS, new guidelines for genetic testing and counselling, an experimental cell replacement strategy, new insights into cellular pathways disrupted in ALS, and more.
We recently developed a research glossary that contains a list of scientific and medical terms and definitions relevant to ALS. The glossary was created to support knowledge-sharing by helping to provide clarity around terminology that may be unfamiliar to our readers. Click here to download a copy.
Uncovering early blood biomarkers for ALS: A promising step towards timely intervention
Researchers have identified specific blood biomarkers that may signal changes prior to symptom onset in ALS.
Multiple lines of evidence suggest that metabolic alterations occur several years before the onset of ALS symptoms. For example, a previous study showed a consistent reduction in metabolic activity among presymptomatic ALS gene mutation carriers compared to healthy controls.
In this UK-based study, researchers analyzed blood tests obtained during routine health screenings from individuals who later received an ALS diagnosis. Using complex statistical methods, they compared a range of blood markers, including cholesterol levels and triglycerides, with those from a healthy control group. The analysis revealed a pattern: individuals with ALS experienced metabolic changes, specifically a decline in both total cholesterol and low-density lipoprotein cholesterol, well before the onset of symptoms and several years ahead of their formal diagnosis. Notably, in recent years, other research groups have identified altered, but different, metabolic markers prior to symptom onset.
While researchers note that further studies are required to better understand the relevance of these findings at the individual level, the results provide further evidence for the existence of a presymptomatic phase in ALS characterized by metabolic changes. The ultimate goal is to discover a highly sensitive early warning signal for ALS, so that intervention can take place before irreversible motor neuron damage occurs. This work represents an important step in that direction.
With increasing knowledge of the genetic causes of ALS, research centered on the presymptomatic stage has become a prominent area of interest in the field. ALS Canada recently sponsored and participated in a workshop co-hosted by the ALS Hope Foundation and Genetic ALS & FTD: End the Legacy that focused on identifying gaps in knowledge in this area and developing guidelines for the clinical management of individuals genetically at risk for ALS. This shift in thinking, with a strong focus on the presymptomatic phase, is critical to reshaping the way we approach ALS treatment in the years ahead.
Development of genetic testing guidelines for ALS to promote standardized care and support
An expert panel have developed guidelines to support all stakeholders in the ALS community in navigating the benefits and challenges of genetic testing.
Significant strides have been made in unraveling the genetic underpinnings of ALS. Earlier this year, the FDA granted approval for the first targeted genetic therapy, known as tofersen or Qalsody, designed to treat SOD1-linked ALS. Genetic factors have also been shown to play a role in some sporadic (non-inherited) ALS cases. As research and care in this area continue to advance, it’s critical that genetic testing practices keep up with these developments.
In this study, researchers used a systematic approach to develop a set of guidelines to improve and standardize genetic counselling and testing practices among healthcare providers. A total of 35 guideline statements were developed. Briefly, the guidelines recommend that all people living with ALS should be offered genetic testing for, at a minimum, the four most common ALS genes: C9orf72, SOD1, FUS, and TARDBP. Specific education and risk assessments that should be provided before and after testing are also identified, along with instructions for laboratories conducting the tests.
These evidence-based guidelines will help to ensure that everyone involved in the ALS community better understand the advantages and complexities of genetic testing. With gene-targeted clinical trials ongoing for several other ALS-associated genes, these guidelines are timely and will help to promote fair access to genetic testing and gene-targeted treatments when available (and applicable). In line with the rapid advancements in this area, ALS Canada is working to develop a central hub on our website to provide more comprehensive and centralized information on ALS genetics. Stay tuned for more information.
Advances in a cell replacement strategy to restore neuromuscular function in ALS
Scientists have developed a technique to transplant healthy nerve cells into mice with an aggressive form of ALS.
The neuromuscular junction (NMJ) is a vital connection point where motor neurons, the nerve cells responsible for voluntary muscle movements, communicate with muscle fibers. Many researchers believe that one of the earliest events in ALS is the detachment of motor neurons from muscle fibers at the NMJ.
In this study, researchers set out to develop a strategy to help restore muscle function in ALS. Using a mouse model, healthy motor neurons derived from stem cells were placed near target muscles. The transplanted neurons were able to form connections with nearby muscle cells, however, they were not integrated into the body’s natural neural pathways through the brain and spinal cord. As a result, external activation was required to stimulate these neurons to pass signals to muscle cells, and this is where a technique called optogenetics played an important role. Using this technique, researchers were able to trigger motor neuron activity by shining a specific type of light on the cells.
Initial experiments faced challenges with the immune system attacking the transplanted cells, however, a specific therapy called H57-597 prevented rejection and allowed healthy connections to be made between neurons and muscles. With regular stimulation, researchers found that muscle connections in the mice grew stronger, resulting in more powerful muscle movements and reduced muscle wasting.
Though these findings are interesting, it’s important to note that the research was conducted in mice, and further studies are needed to determine if this approach can be translated to humans. The long-term vision involves the potential use of implantable devices to deliver the required external stimulation for muscle activity. Ultimately, this work offers hope for the development of a novel cell therapy that could potentially benefit people living with ALS in the future.
Insights into the role of NEK1 and its therapeutic potential in ALS
New research uncovers the cellular pathways affected by NEK1 gene mutations in ALS, providing important foundational knowledge for considering NEK1 as a future therapeutic target.
In 2016, an international team of researchers, including Canadian scientists, first identified NEK1 as a gene associated with ALS. Mutations in NEK1 account for 2 to 3% of both familial and sporadic ALS cases. Yet, the mechanisms through which these mutations contribute to motor neuron dysfunction remain unknown.
In this study, researchers utilized motor neurons derived from individuals carrying NEK1 mutations and fruit flies to model the disease. The results showed that NEK1 mutations disrupt two vital cellular pathways: the microtubule cytoskeleton and nucleocytoplasmic transport (NCT). NEK1 mutations were found to interfere with the function of microtubules, which are essential components to maintaining the structural integrity of a cell. Furthermore, these mutations were found to also affect NCT, a process that involves the exchange of substances between two important compartments of the cell – the nucleus and cytoplasm. Both pathways play a critical role in ensuring the cell’s survival and have been implicated in ALS in many other studies.
Specific anticancer medications, like paclitaxel and the experimental treatment laulimalide, are known to halt cell division by stabilizing microtubules. The researchers decided to test the potential of these drugs in the context of ALS and found that these compounds were effective in restoring the deficits linked to NEK1 mutations in both pathways. This suggests a possible connection between the two cellular processes.
It’s important to emphasize that these cancer drugs can be highly toxic, with a lengthy list of side effects, and may not be suitable for ALS treatment. Nevertheless, this study provides valuable insights in the role of NEK1 in ALS and provides proof-of-concept that stabilizing microtubules could hold potential as a therapeutic approach for ALS. Researchers are now working to better understand exactly how NEK1 regulates these pathways in human neurons, which is important to inform future treatment strategies.
New research sheds light on widespread RNA and protein misplacement in ALS
A new study reveals that protein and mRNA mislocalization within ALS-affected motor neurons may be more widespread than previously thought.
In ALS, proteins like TDP-43 often move from their usual location in the cell’s nucleus (the central hub housing DNA) to the cytoplasm (the region outside the nucleus), where they tend to aggregate into clumps and no longer function properly. Recent findings suggest that this misplacement issue is widespread, extending beyond a few proteins and including mRNA molecules, which play an important role in delivering instructions for protein synthesis from DNA located within the nucleus.
In this study, researchers used stem cells derived from ALS patients with mutations in two ALS-linked genes, TARDBP and VCP, to create motor neurons in the lab. They separated the cell into its two primary compartments, the nucleus and the cytoplasm, and analyzed the distribution of both mRNA and protein within each. They discovered that the ALS-affected motor neurons exhibited significant mislocalization of hundreds of mRNAs and proteins compared to healthy cells.
The movement of these mRNAs and proteins between the nucleus and cytoplasm hints at issues with the cell’s internal transport mechanisms. Additionally, the mislocalized mRNAs and proteins tended to interact more with each other compared to their correctly positioned counterparts. This suggests that as these mRNAs and proteins mislocalize, they might inadvertently drag each other along, creating a domino effect within the cell.
In an attempt to restore normal protein and mRNA localization, researchers tested an experimental therapy called ML240, which is designed to block the activity of the VCP enzyme. They found that it partly corrected mislocalization and reduced DNA damage, indicating that VCP inhibition may have therapeutic potential in ALS.
The researchers note that future studies are needed to validate these findings in different ALS genetic backgrounds and models. Regardless, this work represents a shift in our understanding of ALS, revealing that it involves not just the abnormal movement of a handful of proteins, but rather the widespread mislocalization of numerous proteins and mRNAs, opening up new avenues for research and potential treatments.
