Welcome to the May 2020 ALS Research Update. During these times of uncertainty, it’s reassuring to know that ALS research developments continue around the globe. This month you’ll learn about progress researchers have made in advancing new treatment strategies; developing laboratory models to better understand ALS; and learning how ALS develops and progresses in the body.
Canadian researchers make significant contributions to the clinical and biological understanding of ALS
Already this year, Canadian ALS researchers have made significant contributions to the global understanding of ALS. Here are just a few examples of the innovative discoveries that Canadians have made.
Dr. Yana Yunusova at the Sunnybrook Research Institute and University of Toronto led a study analyzing speech for earlier detection of bulbar ALS. Changes in speech or swallowing abilities are common symptoms of bulbar ALS. Study participants were asked to read specific passages and the recordings were analyzed for speech measures, such as speaking rate and pause timing. The researchers found that by using this technique they were able to detect early and progressive changes associated with bulbar ALS prior to the onset of obvious symptoms. Dr. Yunusova will continue to advance this speech work and is supported by a 2019 ALS Canada Project Grant, in partnership with Orangetheory Fitness Canada.
Dr. Richard Robitaille at l’Université de Montréal explored the role that gender may play in the progression of ALS. Gender-specific differences have been identified in ALS patients and in some animal models, however, the mechanisms underlying these differences currently remain poorly understood. In this study, reseachers found that the motor neurons of female mice are more likely to modify their structure in an attempt to compensate for neuronal loss, but that in the end this may actually be more detremental to survival. These findings highlight the importance of further large-scale studies to evaluate sex-specific differences in ALS.
As a result of Canadians’ generosity during the Ice Bucket Challenge, a team of reserchers led by Dr. Melanie Woodin at the University of Toronto have shown that by specifically targeting upper motor neurons in the motor cortex of mice — a region of the brain affected in ALS – they can correct an imbalance of excitatory signals and delay the onset of ALS symptoms. This work was supported through the ALS Canada Research Program, in partnership with Brain Canada (through the Canada Brain Research Fund, with support from Health Canada).
Finally, a team of researchers led by Dr. Christine Vande Velde at l’Université de Montréal investigated the interactions of an ALS-linked protein called SOD1 on a cellular level. Mutations in SOD1 represent the second most common genetic cause of ALS. Using a rat model, the researchers found that interaction with a specific protein, called TRAF6, promoted the toxic clumping of SOD1 linked to ALS. This is another important piece of the puzzle that will help researchers to better understand the biological pathways responsible for this disease.
Researchers explore a new treatment strategy for a genetic form of ALS
A preliminary study has shown that antibodies designed to target specific proteins in the brain could be helpful in treating a genetic form of ALS.
Antibodies are proteins produced by the immune system to protect the body against foreign invaders like bacteria and viruses, and work by binding to specific proteins on harmful agents and triggering their removal and/or destruction.
The study, which was recently published in the journal Neuron, focused on an antibody designed to target specific proteins, called dipeptide repeat (DPR) proteins, that result from the genetic mutation most common in ALS. These DPR proteins have been shown to build up in the brains of people with C9orf72-linked ALS, however, the exact role they play in disease is currently unclear.
Using cells from healthy elderly blood donors, researchers were able to develop an antibody that was able to cross the blood-brain barrier, bind to specific target proteins in the brain and, as a result reduce toxicity and improve survival in mice. The team of researchers, located in the United States and Switzerland, call this a “proof of concept” study, stating that the results provide evidence that DPR proteins contribute to disease progression and that antibodies targeting DPR proteins could be developed further as a promising treatment strategy for ALS patients with C9orf72 mutations.
A new animal model uses light to help resea
rchers better understand ALS
Scientists have developed an animal model that allows them to experimentally control the clumping of the ALS-linked protein, TDP-43, using light.
Proteins clumping together is a hallmark feature of many neurodegenerative diseases. For example, in almost all cases of ALS, TDP-43 tends to leave the nucleus of the motor neuron (where it is normally found) and form clumps in the cytoplasm. It is not yet known, however, whether these clumps contribute to disease progression, are a byproduct of cellular dysfunction or are protective.
In order to better understand the role of TDP-43 in ALS, researchers developed a zebrafish ALS model with an engineered form of TDP-43 that responds to blue light stimulation by moving from the nucleus into the cytoplasm (as seen in ALS). Zebrafish are very small animals, only about six centimetres long, and are excellent models for studying ALS. They grow into adults within a few days, so research experiments can be conducted quickly. They are also transparent, allowing researchers to use techniques like light stimulation described above to examine their anatomy in fine detail using a microscope.
The results from this Japanese study were recently published in the journal Nature Communications, and showed that prolonged light exposure caused TDP-43 clumping and led to the fish’s neurons becoming smaller with a decrease in muscle innervation (meaning the number of connections between the nerve and muscle cells). The data suggests that TDP-43 clumps in the cytoplasm do in fact contribute to disease progression in these animals.
The researchers hope to expand on this work to include a search for small molecules that may be able to restore a normal balance within motor neurons and could one day serve as a potential treatment for ALS.
The role of nucleocytoplasmic transport in C9orf72-linked ALS
New research coming from the United States provides insight into disrupted nucleocytoplasmic transport in C9orf72-linked ALS.
Growing evidence suggests that a cellular trafficking process called nucleocytoplasmic transport (NCT) is disrupted as a result of mutations in C9orf72. NCT involves the exchange of substances between two important compartments of the cell, the nucleus and cytoplasm, and is crucial to cell survival. The mechanism(s) for this disruption, however, remains unclear.
A new study, published in the journal eLife, revealed that NCT disruption may be linked to specific proteins, called dipeptide repeat (DPR) proteins, that are produced in cells as a result of mutations in C9orf72. These proteins interfere with “cargo loading” at the region where substances normally cross the nuclear membrane. The researchers also found that this disruption can be reversed by supplementing cells with additional healthy RNA, an important natural substance created from DNA. This suggests that RNA-based therapeutic strategies may be able to help restore normal trafficking within cells.
A separate study, published in the journal Neuron, explored the downstream effects of altered NCT. The researchers identified 126 proteins that were distributed differently within cells as a result of the ALS-related trafficking defect. One protein called eRF1, was shown to influence both the reading of RNA (to make proteins) and the degradation of toxic RNA (produced in cells as a result of the C9orf72 mutation). The researchers are hopeful that finding a way to trigger this degradation pathway could be a new therapeutic avenue to explore for the treatment of ALS.
Astrocytes may play an important protective role in the early stages of ALS
Data shows that astrocytes are less vulnerable to the toxicity associated with TDP-43 clumps and may help protect motor neurons from similar damage.
Astrocytes are specialized support cells in the brain with a wide range of functions; you can think of them like personal assistants. ALS research has traditionally focused on motor neurons because these are the cells lost during disease progression, but this research demonstrates that there is still much to be learned about the role of astrocytes in ALS.
In order to learn more, a team of researchers from the United Kingdom and Taiwan developed a cell-specific disease model by collecting skin cells from volunteers. These skin cells were transformed into stem cells which were then turned into either motor neurons or astrocytes. This allowed the researchers to study the interplay between motor neurons and astrocytes in conditions that closely resemble what happens in humans.
In this study, which was recently published in the journal Brain, researchers exposed both cell types to toxic TDP-43 clumps and found that the clumps spread more easily in motor neurons compared to astrocytes. The motor neurons were also more likely to die as a result of exposure to the toxic protein clumps. However, when researchers combined motor neurons that had been exposed to TDP-43 clumps with astrocytes that had not, they found it reduced the level of toxicity in the motor neurons suggesting that astrocytes may have a protective effect. The researchers believe that finding a way to harness the protective properties of astrocytes could pave the way for new treatments.
