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 March 2022 Research Update, you’ll learn about advancements in our understanding of risk factors for ALS, a new platform designed to accelerate translational ALS research in Canada and beyond, progress in developing an ALS-specific tool to measure health-related quality of life, and a high-resolution technique that allowed researchers to visualize human TDP-43 aggregates for the first time.
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.
New insight into how a genetic risk factor for ALS may contribute to disease
Two independent teams of researchers have uncovered how TDP-43 dysfunction, a common feature in more than 97 per cent of ALS cases, may be linked to one of the strongest genetic risk factors for ALS, a gene called UNC13A.
One of TDP-43’s major functions within cells is the processing of molecules called messenger RNA (mRNA), which serve as the genetic blueprint for making proteins. When TDP-43 moves from the nucleus (where it is normally found) to the cytoplasm, a hallmark feature of ALS, it is no longer able to perform its normal function effectively. Researchers have found that when TDP-43 levels in the nucleus are reduced, the mRNA molecules for several different genes are altered. How exactly these changes contribute to disease, however, was largely unknown.
In a pair of studies (1,2), researchers showed that one of the genes most significantly affected by TDP-43 dysfunction is UNC13A. The protein created from the UNC13A gene is known to play a role in synaptic function, the place where neurons communicate with one another, and variations in this gene have been shown to be a risk factor for ALS. The observed changes in UNC13A mRNA resulting from TDP-43 dysfunction cause less of the normal protein to be made within cells which could negatively affect neuronal function. Additionally, researchers found that when the variations in the UNC13A gene linked to a greater risk for ALS were present, this worsened the detrimental effects of TDP-43 dysfunction on UNC13A mRNA and could explain the increased risk for disease.
Through this work researchers have identified a direct functional link between one the strongest genetic risk factors for ALS and TDP-43 dysfunction. Previous findings (3,4) show a similar pattern of events for another ALS-linked gene, called STMN2. Researchers are hopeful that methods to restore the normal function of genes impacted by TDP-43 dysfunction, such as UNC13A and STMN2, represent promising new avenues to explore for biomarker and therapeutic development.
Launch of CAPTURE ALS: the comprehensive analysis platform to understand, remedy and eliminate ALS
The team behind CAPTURE ALS recently published an article detailing the infrastructure, operating procedures, and long-term vision of the platform, which is designed to facilitate and accelerate translational ALS research in Canada and beyond.
Understanding why ALS is different in each person – or the clinical heterogeneity – is vital to effectively treat the disease. The ability to define the unique clinical, genetic, and biological factors at play for each person living with ALS would certainly accelerate the development of effective biomarkers and treatments. CAPTURE ALS, a Canadian platform conceived to unite patients, physicians, and researchers to study ALS, will provide the systems and tools necessary to collect, store, and analyze vast amounts of information about ALS, allowing researchers to create the most comprehensive biological picture of people living with ALS to date.
CAPTURE ALS will initially launch at four Canadian ALS research centers (University of Toronto, McGill University, University of Alberta, and Université Laval). The protocol involves four study visits at 0, 4, 8 and 12 months. At each visit a complete neurological exam, ALSFRS-R score, cognitive panel, speech analysis and neuroimaging scan will be performed. Blood will also be collected with the option to donate cerebrospinal fluid (CSF) as well.
Phase 1 of the project, which includes recruitment of the first 100 people living with ALS (and related diseases) and 25 healthy controls, is expected to launch in March 2022 and was made possible through the financial support of Brain Canada through the Canada Brain Research Fund (CBRF), and of ALS Canada, Alnylam Pharmaceuticals and Regeneron. The Calgary Flames Foundation also donated an additional $240K in December 2021 to support an additional 20 people living with ALS to participate. In phase 2, the team hopes to increase the size and scope of the project by expanding to additional centers and capturing more information such as electrodiagnostic and wearable device data.
The comprehensive data set collected through the CAPTURE ALS platform will aid in the global effort to identify unique subtypes of ALS, enhance the development of both diagnostic and prognostic biomarkers, and inform personalized medicine strategies for the future. For more information, please visit the CAPTURE ALS website.
TDP-43 aggregates from the human brain visualized for the first time
A team of researchers have determined the structure of TDP-43 aggregates obtained from the donated brains of two ALS patients with frontotemporal dementia (FTD).
A hallmark feature of ALS is the formation of abnormal aggregates, or clumps, of the protein TDP-43 within motor neurons. TDP-43 aggregates are also observed in FTD, a related disorder that affects approximately 15 per cent of people living with ALS, with some cognitive symptoms detectable in as many as 50 per cent. Until recently, the exact structure of these potentially toxic TDP-43 aggregates was unknown, which has hindered efforts by the scientific community to develop diagnostic and/or therapeutic tools related to the protein.
In a new study, researchers used a high-resolution technique called cryo-electron microscopy to visualize the detailed structure of these aggregates. The unique shape identified revealed previously unknown binding sites that can be used by researchers to identify new compounds with potential as future treatments. The observed structure also provided clues that a prion-like mechanism may contribute to ALS progression, with TDP-43 aggregates in one region of the brain causing more aggregates to form in neighboring regions.
As TDP-43 is a critical marker of almost all cases of ALS, the structural information obtained in this study will provide a foundation for new ways to diagnose and treat the disease. Additionally, this work will allow researchers to more accurately model human TDP-43 aggregation in the lab which is vital to enhancing our understanding of the molecular pathways that underlie both ALS and FTD.
An ALS-specific tool to measure health-related quality of life
The ability to assess health-related quality of life is vital as it can provide clinicians with a quantitative measure to understand the impact of ALS and its treatment, compare different therapeutic interventions, predict outcomes, and incorporate patient perspectives into the evaluation of care plans.
Currently, no available assessment tool has been developed in collaboration with Canadians living with ALS that sufficiently accounts for or values their needs and preferences. Generic tools may not capture areas important to specific diseases and often tend to focus on physical factors rather than whether care plans are meeting an individual’s goals.
In this study, researchers outline their progress in developing a preference-based ALS health-related quality of life scale (PB-ALS HRQL scale). With input from Canadians living with ALS, the team presents a scale comprised of eight items identified as being important to the patient community, which includes recreation and leisure, mobility, interpersonal interactions and relationships, eating and swallowing, handling objects, communicating/speech, carrying out routine activities, and mood.
The ultimate goal of this work is to provide the ALS community with a tool that can measure overall health status in a way that takes into account patient preferences. This will help to support clinicians in developing and adjusting care plans that maximize function and independence, manage symptoms, and address the needs of Canadians living with ALS. The next step in this work, which is supported by a 2018 ALS Canada Project Grant, is to translate the PB-ALS HRQL scale into French and develop a scoring algorithm that weights each domain based on patient preference.
Further exploration of potential risk factors for ALS
Large scale analyses of complete sets of DNA, or genomes, from people living with ALS reveal potential genetic and environmental risk factors for disease.
DNA holds the master code of genetic instructions that oversee the production of proteins, which are the workhorses of the cell. Environmental impacts can make changes to our DNA that affect how our genes are expressed. For example, environmental stress can leave tags in specific locations on DNA through a process called methylation. This process modifies the genetic instructions, which in turn changes how much protein is produced and ultimately can influence a variety of different processes within the body.
With today’s advanced technology, scientists can see the locations where methylation of DNA occurs from blood samples. In a recent study, which involved 76 different researchers from 16 different countries, including Canada, blood samples from 6,736 people living with ALS and 2,943 healthy controls were analyzed. Researchers identified 42 genes that had a different methylation pattern in people living with ALS compared to controls. These genes were linked to cellular pathways involved in metabolism, cholesterol biosynthesis and immunity.
Further analyses revealed that high-density lipoprotein cholesterol, body mass index, white blood cell proportions, and alcohol intake may be risk factors for ALS. Researchers found that cholesterol biosynthesis was the most strongly linked to disease. A similar finding came from a separate study, which analyzed the genomes of 29,612 people living with ALS and 122,656 controls, where researchers also noted a link between high cholesterol levels and ALS.
Researchers noted that the results obtained from this study cannot explain the causes of ALS, which are likely influenced by a complex interplay of genetic, environmental and lifestyle risk factors, and that we should be cautious in concluding that the factors identified represent major risk factors for disease. However, the pathways identified may help to uncover disease-relevant mechanisms that could be targeted and modified to help slow or stop the progression of ALS.
