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 – you can read the previous one, from August 2017, here.

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 people may be interested in the original source papers. While abstracts are always available, since many journals are subscription based in some cases full papers may only be accessed at a cost.

Posted in: Research