Within the brain and spinal cord, neurons pass electrical signals to each other through specialized chemicals called neurotransmitters. When this signalling network functions properly, there is a good balance between chemicals that excite the neurons and chemicals that inhibit them. Both excitation and inhibition are necessary for the brain to function normally and send signals throughout the body to generate complex movements like walking.
A hallmark feature of ALS before symptoms appear is that motor neurons in the brain become over-excited. This change occurs at the cellular level and can’t be noticed by people who experience it, but researchers have found evidence of over-excitability in both electrical recordings from the brain and the cerebrospinal fluid of people with ALS.
Studying inhibition in ALS
While several ALS researchers are investigating what causes this over-excitation, there are only a few who study the inhibitory system, including Dr. Sahara Khademullah, a postdoctoral fellow working in the lab of Dr. Yves De Koninck at the CERVO Brain Research Centre at Université Laval.
As a PhD student, Dr. Khademullah previously worked in the lab of Dr. Melanie Woodin at the University of Toronto, who was funded by an ALS Canada Brain Canada Discovery Grant at the time. “Dr. Woodin gave me a lot of freedom to ask a lot of unconventional questions and try novel techniques with the goal of uncovering a potential therapy for ALS,” said Dr. Khademullah. Working with Dr. Woodin, she discovered that increasing inhibition in mice before they developed ALS symptoms could reverse some of the neuronal damage and motor deficits associated with the disease.
Most recently, Dr. Khademullah has been working in Dr. De Koninck’s lab on the first study to investigate the role of a protein called KCC2 (potassium-chloride co-transporter 2) in ALS. KCC2 acts like a gatekeeper, controlling whether the electrical signals or neurotransmitters can enter or leave the cell as part of the inhibition process. Lower levels of KCC2 have been found in people with chronic pain syndromes, spinal cord injury, and Alzheimer’s disease, as well as the sporadic form of ALS compared to people without ALS.
To further understand the effects of lower levels of KCC2, Dr. Khademullah and Dr. De Koninck have been investigating mice that have been genetically altered to mimic aspects of the familial form of human ALS to see which motor neurons are affected by the disease, when neurodegeneration first begins to occur, and whether restoring KCC2 levels in the spine and the brain, or both, can halt or reverse ALS disease progression.
Advancing ALS research
Dr. Khademullah recently received a $165,000 trainee award from the ALS Canada Research Program, in partnership with Brain Canada and La Fondation Vincent Bourque, to further investigate how aberrant inhibitory transmission along the pathway connecting the motor cortex to the spinal cord leads to neurodegeneration in ALS and whether she can prevent or delay disease progression in mice.
She hopes to discover when KCC2 levels start to decrease, indicating the ideal timing for treating the mice with an experimental drug called CLP290, which was developed by Dr. De Koninck. “If I can restore the levels of KCC2 with CLP290, I hope to be able to prevent or delay disease onset in mice, or even better, stop progression once it’s initiated,” said Dr. Khademullah.
Ultimately, Dr. Khademullah hopes that her research will find that KCC2 is a viable target for future drug development and that testing its levels in cerebrospinal fluid may one day act as a reliable biomarker for earlier diagnosis and to measure responses to experimental treatments in clinical trials. “Finding a cure for ALS is likely going to need a multidisciplinary approach. Depending on where inhibition fits into the story, we might be able to prolong the lifespan and increase the quality of life for people living with ALS,” said Dr. Khademullah.
“A lot of my passion and drive comes from the realization that people living with ALS have extremely limited options and are putting their faith in researchers and doctors to help them in their quest to end ALS,” Dr. Khademullah said. “Every day that I’m at work, my goal is to try to find answers that will help.”
Dr. Khademullah’s trainee award is generously supported through a partnership with La Fondation Vincent Bourque, which was established shortly before Mr. Bourque’s passing in November 2018. Mr. Bourque was diagnosed with ALS in 2015 at the age of 40. As a strong advocate for supporting ALS research, he understood that future advancements in research are limited by the amount of funding available. This led to the creation of a family foundation to support the acceleration of research with the hope of finding a cure.When the Bourque family was introduced to the work being done by Dr. Khademullah, they saw an opportunity to support the next generation of dedicated ALS researchers in Canada in the pursuit of a future without ALS.“The progress of research in recent years has brought hope to those living with ALS that life-changing treatments could be possible,” shared Isabelle Lessard, co-founder of La Fondation Vincent Bourque. “We are proud to be helping to build the capacity for future ALS research discovery by supporting Dr. Khademullah’s research as part of Vincent’s legacy.”