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 roadmap of the 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 first installment for 2018 – for more information see past updates from August and November 2017.

New insights into a possible link between chronic traumatic encephalopathy and ALS

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease that results from multiple head injuries and is often associated with athletes involved in contact sports, such as football or hockey, or people who have completed military service. Approximately 4 to 6 percent of people living with CTE will also show symptoms of ALS (referred to as CTE-ALS). Since this percentage is much greater than the occurrence of ALS in the general population (which is only approximately 0.1%), it suggests a potential link between CTE and ALS. In order to determine what this link may be, researchers from Western University analyzed post-mortem brain and spinal cord samples from people who lived with CTE, CTE-ALS and healthy controls. The researchers specifically looked at a protein called tau, which is commonly found in the brain. In people with CTE or CTE-ALS researchers observed the same buildup of abnormal tau clumped together in cells. In both cases, a tag found on the tau protein indicated that a specific biological pathway that leads to cell death had been activated. In a previous study, however, the researchers showed that specific medications may be able to prevent activation of this pathway. Taken together, the results of this study provide evidence for a biological link between CTE and CTE-ALS, as well as a new target for developing drug therapies for both conditions.

ALS research using animal models helps to identify new treatment targets

In 2011, mutations in a gene called C9ORF72 were identified as the most common genetic cause of ALS. The C9ORF72 gene normally contains a short repeating segment of DNA that, in some people living with ALS, is drastically expanded with up to hundreds or thousands of repeats observed. Two substances (referred to as repeat RNAs and DPRs) are produced in cells as a result of these expansion mutations. To determine if and how either of these substances contribute to disease, a team of researchers from Belgium used an ALS animal model to replicate disease. In this study, small fish (zebrafish) were genetically altered to carry C9ORF72 expansion mutations. When studying these fish, researchers found that both substances were toxic and can lead to cell death independently of one another. This study has significant implications for drug discovery as it shows researchers that treatments designed to simultaneously neutralize both substances will likely be more effective than treatments that target only one. Previous studies using animal models to better understand ALS have shown promise in developing new treatments. For example, a drug called pimozide shown to have a positive effect in worms and fish has now moved to a Phase 2 clinical trial with funding support from ALS Canada to determine if it may be effective at slowing the progress of ALS in humans.

The role of cellular “traffic jams” in ALS

Within the jelly-like interior of a cell, referred to as the cytoplasm, lies a round structure called the nucleus. This is where genetic information (DNA) is housed. A barrier that surrounds the nucleus selectively allows important molecules to cross either in or out of the nucleus, depending on the direction. This process is referred to as nucleocytoplasmic trafficking and is vital to cell survival. Previous studies have shown that nucleocytoplasmic trafficking is disrupted in the motor neurons of people who have a form of ALS linked to mutations in the C9ORF72 gene. However, scientists at the Emory University School of Medicine and Mayo Clinic in Jacksonville, Florida have found that this cellular “traffic jam” may not be limited to just C9ORF72-linked ALS. In approximately 97% of ALS cases, a protein called TDP-43 shows abnormal behavior in cells. TDP-43 is supposed to be located in the nucleus but in the motor neurons of people with ALS it is often found clumped together in the cytoplasm where it does not belong. Researchers analyzed the composition of these clumps and found that in addition to TDP-43, proteins that play an important role in nucleocytoplasmic trafficking were being held “hostage” and unable to complete their intended functions. The study suggests that treatments aimed to break up the TDP-43 clumps found in nearly all ALS cases and restore normal cellular trafficking may represent an effective new strategy to treat all forms of ALS.

How targeted genetic screening can increase our understanding of ALS

Proteins are often referred to as the workhorses of the cell as they complete nearly all cellular functions required to sustain life. Instructions located in a person’s genes (subunits of DNA) direct which proteins are formed in cells and when. Mutations in genes can cause disease by either preventing protein formation or altering protein function. In a November 2017 study, researchers with the Project MinE ALS Sequencing Consortium set out to identify genetic mutations that may lead to ALS. By completing a targeted genetic screen analyzing 274 proteins pre-identified to have a high chance of being associated with ALS, researchers found 90 previously unknown and rare mutations linked to ALS. Of the 103 people living with ALS whose DNA was read, 6 carried more than one known genetic mutation. For these people, researchers found that if the proteins produced from the mutated genes interacted with each other in cells, the disease progressed at a faster rate. In addition to identifying new gene variants linked to ALS, this study showed that in some cases people living with ALS may carry multiple genetic mutations that act together to amplify toxicity. This may help to explain some of the variability in disease symptoms observed among people living with ALS and has important implications for the development of new ALS treatments. Canada is one of the 18 countries participating in the Project MinE Research Partnership and is committed to reading and analyzing up to 1,000 DNA profiles. ALS Canada is leading Canada’s fundraising efforts for Project MinE and our contribution started in 2017 with the first 200 samples. To support Canada’s efforts to contribute to Project MinE, make a donation today.

Scientists identify another cellular pathway that affects TDP-43 toxicity in ALS

Communication within and between cells is a crucial component of life. In order to make this communication possible, there are multiple trafficking systems found within cells that shuttle substances to their required locations. One such system, described earlier, is referred to as nucleocytoplasmic trafficking and involves the movement of substances between different parts of the cell. Another system, called endocytosis, involves the movement of substances from outside the cell into its interior. A study from a University of Arizona research team identified endocytosis as another cellular trafficking system that is disrupted in ALS. Using yeast cells genetically modified to produce faulty TDP-43, researchers found that when endocytosis was disrupted, TDP-43 formed larger toxic clumps within cells. On the other hand, when endocytosis was boosted in a fruit fly model of ALS, researchers observed decreased neurodegeneration and increased movement. The results of this and other studies indicate that not one, but rather multiple cellular trafficking systems may be disrupted in ALS. Learning more about these trafficking mechanisms may help researchers to find an effective treatment for the disease. The ALS Canada Research Program is currently funding a project examining the role of C9ORF72 in endocytosis mechanisms with the hope of gaining a better understanding of the altered trafficking processes that may underlie 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