Microglia are the primary immune cells of the brain and spinal cord. They patrol the central nervous system to track down and dispose of unwanted cellular debris and dead neurons, as well as organisms like bacteria and viruses that pose a threat of infection. When they detect invaders, they change their behaviour to summon the body’s immune response to take care of the problems. After the issues are resolved, the microglia return to their resting state.

However, in many neurodegenerative diseases like ALS, microglia can become chronically overactivated and toxic to neurons. “The chronic activation is like your computer freezing when you have too many browser tabs open,” explained Dr. Jasna Kriz, a senior scientist at the CERVO Brain Research Centre at Laval University. “When the microglia are constantly activated and can’t return to a resting state, they become overwhelmed, stop responding and prevent the right immune responses from happening.”

A new protein discovery

Back in the early 2000s, scientists tested an existing bacterial antibiotic drug called minocycline in human clinical trials to see if it could reduce inflammation and immune responses and therefore slow the progression of ALS in people living with the disease. The trials were not successful. One of the reasons why the drug did not perform as expected was because it worked in a general fashion and did not target the specific mechanisms of inflammation and immune responses seen in ALS.

A postdoctoral student at the time, Dr. Kriz wanted to find out why something that worked so well in three independent lab studies had failed in human clinical trials. She started her own lab and since then, her research has focused on studying the interaction and processes that occur between immune cells and neurons. Some of her previous research has been funded through the ALS Canada Research Program.

Dr. Kriz recently discovered that a protein called serine/arginine-rich splicing factor 3 (SRSF3) can block the genes of the microglia from making the right proteins to support a healthy immune response. It can cause microglia to transform from their usually helpful, healthy state, into abnormal, chronically-activated cells that become toxic to neurons.

Her preliminary research with mice that were genetically altered to model the SOD1 form of human ALS demonstrated this same disrupted immune response in microglia. Additionally, through a collaboration with Dr. Angela Genge, director of the ALS Clinic at the Montreal Neurological Institute and Hospital at McGill University, Dr. Kriz discovered an increase in SRSF3 activity in the cerebrospinal fluid of people with sporadic ALS but not in people without ALS in a small exploratory study.

Advancing ALS research

With a $125,000 project grant from the ALS Canada Research Program in 2018, Dr. Kriz will investigate further how SRSF3 prevents a healthy immune response and how that process may be involved in ALS. She will conduct lab experiments using cultured microglia from adult SOD1 mice as they are excellent models of human ALS progression and the immune system.

“My hypothesis is that by changing the activity of SRSF3, I will be able to completely reprogram the function of the microglia and slow down disease progression in ALS,” said Dr. Kriz. “What’s particularly interesting is that SRSF3 is only activated at the time the microglia are changing. If we can block that action, the microglia should remain normal longer, slowing the disease.”

Dr. Kriz will try to change the activity of microglia in ALS mouse models with two types of drugs. The first is a drug called a kinase inhibitor, which is already known for its ability to reduce SRSF3 activity in leukemia, a form of blood cancer. The second approach is an experimental “gene-silencing” drug called an antisense morpholino that Dr. Kriz developed in her lab. She hopes that it will reduce the production and activity of SRSF3 and therefore restore a more normal immune response.

If successful, Dr. Kriz hopes that SRSF3 activation will be an exciting new target for future drug development for ALS. “I’m excited that I discovered a mechanism that operates at a time when the disease is already clinically active. That means it may be possible to develop a therapy in the future to help people who already have ALS,” said Dr. Kriz.

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 panellists 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.

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Posted in: Research