ALS is a disease that gradually paralyzes people as motor neurons lose their ability to communicate with the muscles of the body and eventually die. But the problems are not only caused by changes inside motor neurons: the cellular environment around the motor neurons can contribute significantly to disease progression.

Microglia are the immune cells of the central nervous system, found throughout the brain and spinal cord. They usually play a protective role, but if over-activated, they can become toxic to motor neurons. One theory is that the over-activation of microglia in people with ALS may enhance progression of the disease.

Dr. Stefano Stifani, a scientist at the Montreal Neurological Institute and Hospital at McGill University in Montreal, Quebec, has been studying motor neuron development and function for over a decade. He recently received a $124,930 grant from ALS Canada to examine the communication processes between microglia and motor neurons.

In this project, Dr. Stifani will capitalize on two scientific advancements. The first is the ability to grow almost any cell type in the body using induced stem cells derived from skin or blood samples, one of the greatest scientific achievements in the past decade.

Just over a year ago, scientists reported for the first time the successful generation of human microglia using induced stem cells. “As soon as the technology to derive microglia from induced stem cells became available, we immediately established a collaboration with one of the four initial pioneers of that discovery, Dr. Valentina Fossati at the New York Stem Cell Foundation Research Institute”, Dr. Stifani said.

Thanks to this scientific collaboration, Dr. Stifani’s laboratory has implemented protocols of human microglia derivation to add to their existing expertise in growing motor neurons from people with ALS using induced stem cells. These efforts are building on capacity gained through a separate project made possible by an ALS Canada-Brain Canada Arthur J. Hudson Translational Team Grant awarded in 2016.

The second scientific advancement involves specially-designed little boxes called microfluidic chambers that allow scientists to grow different cell types in separate compartments. The compartments keep the cell types apart, but tiny grooves let them communicate with each other so that it is possible to study the effects of localized changes. Dr. Stifani will grow the microglia and motor neurons from induced stem cells obtained from skin or blood samples provided by people with familial forms of ALS including those with SOD1, FUS, and C9orf72 gene mutations.

One of the main benefits of using microfluidic chambers is that Dr. Stifani will be able to conduct a range of experiments with changing conditions for the microglia, the motor neurons, or both, in order to see what happens. He will also compare the results to cells that do not have ALS gene mutations. One way in which he plans to alter the communication processes between the cell types is by changing the activity of nuclear factor kappa B (NF-kB), a protein known to play a role in increasing inflammatory processes in microglia as well as driving motor neuron degeneration in ALS.

“We hope to determine whether injured human motor neurons send signals to microglia to activate immune responses and see if changes in NF-B activity affect that communication,” Dr. Stifani explained. “If increased activity of NF-B contributes to accelerating the toxic effect of microglia in the presence of ALS mutations, then decreasing that activity could prove to be an important new target for future drug development.”

In keeping with the mandate of the Montreal Neurological Institute and Hospital to become the first Open Science Institute in the world, Dr. Stifani plans to share information, cell cultures and experimental data with other interested researchers in the global ALS research community.

If Dr. Stifani can successfully identify the mechanisms of communication between human microglia and motor neurons and find a way to change that process during ALS disease progression, he anticipates that pharmaceutical companies may be very keen to use the ALS patient-derived motor neuron and microglia co-culture systems in future drug discovery programs.

This research project is one of 12 funded by the ALS Canada Research Program in 2017 following a rigorous scientific assessment by panels of global ALS experts. The panelists evaluated a larger pool of applications to identify the projects that are grounded in 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.

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