Category: For Health Care Professionals

ALS manifests very differently among people who develop the disease. It can occur anytime in adulthood. People usually only live two to five years after diagnosis, but it can range from six months to more than 20 years. Some people living with ALS, about 30 to 50 percent, experience cognitive or behavioural difficulties. Why does the disease affect people so differently?

Dr. Ekaterina Rogaeva, a geneticist at the Tanz Centre for Research in Neurodegenerative Diseases at the University of Toronto, believes the answer may lie in how environmental factors modify DNA as people age. Her research has focused on gene mutations that are associated with movement disorders and dementia, including ALS, Alzheimer’s disease, Parkinson’s disease and frontotemporal dementia.

How environmental factors might modify genes

Aging is the biggest risk factor for developing ALS and other neurodegenerative disorders. We usually count age chronologically, using the number of years since birth, but emerging evidence shows that biological age differs from chronological age. The biological age of our cells may be based on how they have been modified by environmental factors, like exposure to smoking, for example. These environmental impacts can leave marks on DNA without changing its underlying structure in a process called DNA methylation. Using DNA extracted from blood samples, scientists can see the precise locations where age-related DNA methylation occurs and calculate DNA methylation age, which may be an estimate of biological age.

“Most healthy people have a DNA methylation age that is very close to their chronological age,” said Dr. Rogaeva. “But when we look at DNA samples from people recently diagnosed with ALS, we find differences between DNA methylation age and chronological age up to sixteen years.”

Previous insights from studies of identical twins and people with C9ORF72-ALS

Several years ago, Dr. Lorne Zinman observed identical twins with very different disease onset and progression at the Sunnybrook Health Science Centre ALS Clinic. His observation sparked Dr. Rogaeva curiosity to learn more about how this was possible, given that identical twins share almost identical DNA. Together, Dr. Rogaeva, her research associate Dr. Zhang, Dr. Zinman and Dr. Janice Robertson at the Tanz Centre for Neurodegenerative Diseases at the University of Toronto have conducted genetic studies on blood samples from identical twins. In their most recent twin study, one twin had no ALS symptoms but the other had been living with ALS for 17 years, and had a more prominent history of narcotics abuse than the unaffected twin. Overall, they found that the DNA methylation age of ALS-affected twin was five years older than the unaffected twin. Similar findings were observed for another pair of identical twins.

Next, Drs. Rogaeva, Zhang, Robertson and Zinman tested their theory using blood samples from a broader population — 46 unrelated people with the C9ORF72 gene mutation, the most common genetic form of ALS. Again, they found that an accelerated DNA methylation age was associated with an earlier age of onset and a shorter disease progression for ALS and published their findings.

Investigating the theory in sporadic ALS

With an ALS Canada Research Program project grant of $125,000, Dr. Rogaeva will build on these previous discoveries in identical twins and people with C9ORF72-ALS and investigate whether DNA methylation age can also explain differences in disease onset and progression in people with sporadic ALS. Most cases of ALS, about 90 per cent, are sporadic, meaning that they are not linked to an inherited single gene mutation.

Using blood samples and clinical data collected at diagnosis from 250 people with sporadic ALS, Drs. Rogaeva and Zhang will analyze the associations between the signs and symptoms of the disease at diagnosis and DNA methylation levels, including DNA methylation age. If they find accelerated biological age in these samples, they will validate their findings by conducting the same analysis using a large number of DNA methylation profiles collected for Project MinE, a multi-national initiative that aims to sequence and analyze entire DNA profiles collected from 15,000 people living with ALS. ALS Canada is a contributor and is spearheading Canada’s participation in the project.

“My prediction is that accelerated DNA methylation age, as calculated by marks on DNA, is associated with earlier disease onset and faster disease progression,” said Dr. Rogaeva. “From previous work, we know that there are 353 spots within the genome where we can observe DNA methylation age. We will explore whole genomes to see if we can find more spots to add more information for calculating DNA methylation age.”

“If someone were to discuss this concept with me five years ago, I would have said it’s science fiction,” shared Dr. Rogaeva. “But because I can see the link between DNA methylation and ALS in our own dataset and find an association of DNA methylation age with several other neurodegenerative diseases, it reinforces that genetic factors are secondary to age as a risk factor for these diseases.”

It’s important to note that any influence of biological age on ALS is only applicable in those who are susceptible to getting the disease in the first place, likely through a complex set of genetic factors. That said, if DNA methylation age does influence the timing of disease onset and severity of ALS in this broader population of people with sporadic ALS, it may prove to be a valuable tool for further understanding this susceptibility to developing ALS and enable earlier diagnosis, making it possible to treat people with ALS sooner.

This research project is one of 8 research projects funded in 2018 by the ALS Canada Research Program, which is the only dedicated source of funding for ALS research in Canada. The funding of the project followed a rigorous scientific assessment by panels of global ALS experts. The panelists evaluated a larger pool of applications to identify the projects that demonstrate scientific excellence and have the potential to most quickly advance the field of ALS research in order to develop effective treatments.

ALS Canada is a registered charity that receives no government funding. Everything we do – from funding research to providing community-based support for people living with ALS – is possible only because of donor generosity and partnerships with provincial ALS Societies who contribute to the ALS Canada Research Program.

New research from the University of Toronto and the University of Cambridge, funded in part by the Ice Bucket Challenge and the ALS Society of Canada’s partnership with Brain Canada, is having an impact on our understanding of ALS and expanding the pathways for research into ALS treatments.

Published today in Cell, the findings reveal the discovery of a molecular mechanism that may lead to the death of neurons in some types of ALS and frontotemporal dementia. This work advances our understanding of how certain proteins affect nerve cells in people living with ALS and reveals a new area for research that could someday lead to the development of ALS treatments.

It is because of the generosity of donors, partnerships with provincial ALS Societies across Canada and our partnership with Brain Canada, who matched funds committed following the Ice Bucket Challenge, that the ALS Canada Research Program has been able to provide almost twice the level of funding to ALS researchers across Canada. Continued support of the ALS Canada Research Program will significantly accelerate our ability to treat ALS and build the pipeline of significant research discoveries.

For more information on the study, you can read the full article from the University of Toronto Faculty of Medicine. This article was originally posted on the University of Toronto, Faculty of Medicine website on April 19, 2018. Thank you to the University of Toronto for giving ALS Canada permission to re-post this content.

Researchers Find Mechanism Behind Neuron Death in ALS and Dementia

Researchers at the University of Toronto and the University of Cambridge have identified the molecular mechanism that leads to the death of neurons in some types of ALS, or amyotrophic lateral sclerosis, and in a common form of frontotemporal dementia. They have also uncovered novel therapeutic targets for these currently incurable diseases.

The journal Cell published the findings today.

A common characteristic of ALS and frontotemporal dementia is the clumping of misfolded RNA-binding proteins, including a protein called FUS, in the brain and spinal cord. In nerve cells, FUS proteins normally change back and forth from small liquid droplets (resembling oil droplets in water) to small gels (like jelly).

But in ALS and frontotemporal dementia, FUS proteins become permanently stuck as abnormally dense gels, trapping the RNA and making it unavailable for use. This damages nerve cells by blocking their ability to make the proteins needed for synaptic function and leads to the death of neurons in the brain and spinal cord.

“This was a very exciting set of experiments where we were able to apply cutting edge tools from physics, chemistry and neurobiology to understand how the FUS protein normally works in nerve cells, and how it goes wrong in motor neuron disease and dementia,” says Peter St George-Hyslop, director of the Tanz Centre for Research in Neurodegenerative Diseases and a professor of medicine at U of T.

In healthy neurons, the FUS protein condenses (from droplets to gel), captures RNA and transfers it to remote parts of the neuron involved in making connections (synapses) with other neurons. Here, the protein ‘melts’ and releases the RNA. The RNA then helps create new proteins in the synapses, which are essential for keeping the synapses working properly, especially during memory formation and learning.

In frontotemporal dementia, the researchers found that defects in the chemical modification of FUS caused the abnormal gelling. In motor neuron disease, abnormal gelling arose from mutations in the FUS protein itself, which meant it was no longer able to change form. “These findings open up a new avenue of work to identify ways to prevent the abnormal gelling of FUS in motor neuron disease and dementia,” says St George-Hyslop, who is also a professor at the Institute for Medical Research at the University of Cambridge.

The scientists used human cells that resemble neurons, and neurons from frogs, to investigate the regulation of FUS from liquid droplets to small gels — and what makes that reversible process go awry. Potential therapeutic targets include the enzymes that regulate the chemical modification of FUS, and the molecular chaperones that facilitate FUS proteins to change form.

These treatments would need to allow FUS to continue moving between safe reversible states (liquid droplets and reversible gels) but prevent FUS from dropping into the dense, irreversible gel states that cause disease.

“For the past several years, evidence has been growing that understanding these phase transitions could significantly accelerate our ability to treat ALS,” says Dr. David Taylor, vice president, research at the ALS Society of Canada. “The work advances our understanding of this biology and reveals potential molecular targets for exploration, which might someday lead to the development of ALS treatments.”

Taylor notes that the research was possible in part through funding from the Ice Bucket Challenge and the ALS Society of Canada’s partnership with Brain Canada, and he says the findings are an example of why continued investment in research funding is vital.

The research was funded by the Canadian Institutes of Health Research, Wellcome Trust, European Research Council, Swiss National Science Foundation, and the ALS Society of Canada and Brain Canada (through the Canada Brain Research Fund, with support from Health Canada).

*This story was based on a media release from the Wellcome Trust, written by Natalie Hodgson.

ALS research is at a time of unprecedented advancement. New information on genes linked to ALS and the downstream effects of mutations in these genes has helped researchers to develop a so-called ‘roadmap’ of biological pathways that are important in ALS and to gain a better understanding of this complex disease.
With new advancements being announced almost daily, the ALS Canada Research Program team regularly summarizes what we believe are the most significant research discoveries. This is our second installment for 2017.

More evidence that targeting quality control mechanisms within cells could lead to new treatment options for ALS

Abnormalities in a protein called TDP-43 are present in approximately 97 per cent of all ALS cases. TDP-43 is normally found in the nucleus of a cell (a central compartment where our DNA is located); however, in people living with ALS it is often found in the cytoplasm (the area outside of the nucleus) where it does not belong. This is especially harmful because when TDP-43 is in the cytoplasm it clumps together and is no longer able to function properly. In a July 2017 study based in the United States, researchers identified a specific modification to TDP-43 that may be responsible for its abnormal behavior in ALS. Promisingly, they also identified a biological pathway (referred to as the HFS1-dependent chaperone pathway) that may be able to restore the normal function of TDP-43. This pathway can be thought of as a type of “quality control” mechanism within cells that prevents the build-up of toxic protein clumps. In this study, researchers showed that when the HSF1 pathway was stimulated, clumps of TDP-43 in the cytoplasm broke apart. This new evidence strengthens the hypothesis that drugs designed to increase quality control mechanisms within cells represent a promising new therapeutic approach for the treatment of ALS.

Identical twins can help us to better understand ALS

Despite having the exact same DNA, identical twins are not truly identical. This is because not all genes are expressed or “turned on” in the same way in each twin – inconsistencies that are referred to as epigenetic differences. Aging processes and environmental factors (such as smoking or diet) can influence which genes are turned on or off in a person. To determine the role of gene expression in ALS, researchers in Australia conducted a study analyzing five pairs of identical twin siblings. In each case one twin was living with ALS and the other twin was unaffected. Using simple blood tests, researchers analyzed the DNA sequences of each twin pair looking for specific DNA “tags” (referred to methyl groups) that let researchers know when a gene has been turned off. In almost every case, the twin living with ALS showed an increase in age-related DNA tags compared to the unaffected twin sibling suggesting that faster cell aging may play a role in the development of ALS. Further, researchers found widespread differences between twin pairs in the expression of genes linked to two biological pathways that play an important role in neuron health. Overall, the results of the study suggest the environmental factors that alter gene expression may play an important role in development of ALS. Researchers hope that the identification of DNA tags that indicate a susceptibility to ALS could lead to the development of blood-based biomarkers for ALS which would allow for earlier and easier diagnosis, as well as a better understanding of the disease.

Mutations in the protein TIA1 put people at a greater risk of developing ALS

A team of scientists that includes Dr. Ian Mackenzie from the University of British Columbia, as well as a number of other Canadian researchers, has found that mutations in a protein called TIA1 put people at a greater risk of developing ALS. When a cell is stressed by external factors, such as heat, cold or radiation, structures called stress granules form to temporarily protect important elements of the cell. A common component of stress granules is TDP-43, a protein linked to ALS. In a healthy cell, once the stress has passed, the stress granules break up and the cell returns to normal. When studying TIA1, however, researchers found that mutations in this protein prevent the breakup of stress granules. Scientists believe that the abnormal behaviour of stress granules caused by mutations in TIA1 results in important cellular elements, like TDP-43, being trapped in stress granules which can be harmful to cells. The results of this study, which was funded in part by an ALS Canada-Brain Canada Arthur J. Hudson Translational Team Grant, further support the hypothesis that stress granules may play an important role in ALS and provides a new therapeutic target for designing ALS treatments.

A new gene therapy technique that could help to treat ALS

CRISPR/Cas9 is a revolutionary gene editing technique. It was first identified in bacterial cells as part of their immune response to recognize and destroy invading genetic material, for example, from viruses; however, scientists have now adapted this system for use in human cells. CRISPR/Cas9 allows scientists to make specific changes to the DNA of living organisms and experts are now exploring how this technology may help to treat a variety of different diseases, including ALS where mutations in the C9ORF72 gene have been identified as the most common genetic cause. Toxic substances, called repetitive RNAs, produced as a result of C9ORF72 mutations are believed to play a key role in the development of ALS. In an August 2017 study involving collaboration between researches from United States and Singapore, researchers showed that CRISPR/Cas9 can successfully identify and eliminate these toxic RNAs in cells taken from people living with ALS. The promising results from this study conducted on a cellular level indicate to researchers that this technique may one day represent a viable strategy for the treatment of ALS.

The role of protein function in better understanding how ALS works in the body

Once scientists identify genes linked to ALS, they must then identify the biological pathways affected as a result of mutations in these genes in order to ultimately develop new treatments. When scientists first discovered that mutations in a protein called CHCHD10 were associated with ALS they did not know the normal function of this protein or the pathways by which mutations in CHCHD10 promote the development of ALS. By using various models to study the biology of ALS (ranging from nerve cells in a dish, to worms, to mouse brains) researchers can now answer these questions, and found that CHCHD10 serves three very important protective roles. First, it helps to maintain the normal function of mitochondria, structures often referred to as the power plant of cells as they provide cells with the energy needed to survive. Second, CHCHD10 helps to ensure the normal functioning of another protein linked to 97% of ALS cases, TDP-43. Third, it helps nerve cells to pass signals to one another which is essential to the normal functioning of the nervous system. When CHCHD10 is mutated, it can no longer complete any of these protective functions and as a result can promote cell death leading to ALS. These findings highlight the importance of understanding the normal role of proteins within cells to better understand the biology of ALS.

Note: We have included links to the publications because we know you may be interested in the original source papers. While abstracts are always available, many journals are subscription based, and in some cases, full papers may only be accessed at a cost.