Novel approach to ALS research

May 19, 2022

Most ALS research has focused on understanding the role nerve cells called motor neurons play in development of the disease; however, Deepti Lall, PhD, a project scientist in the Cedars-Sinai Board of Governors Regenerative Medicine Institute, decided to take a different approach, according to a news release.

Lall and colleagues examined laboratory mice with a genetic mutation associated with ALS. They discovered immune cells in the brains of these laboratory mice were going haywire and damaging neurons; therefore, she began looking beyond neurons that may help lead to a cure.

There's a huge urgency worldwide to find new therapies that help patients with amyotrophic lateral sclerosis (ALS), a fatal neurological disorder that causes people to eventually lose the ability to walk, talk, eat, and breathe.

ALS attacks nerve cells in the brain and spinal cord that are responsible for muscle control. There is no cure for the disease, and most people die within a few years of being diagnosed. Current treatments may slow down the disease or address symptoms.

When asked about a study published in 2021 that reported the brain's immune cells may play a role in ALS and frontotemporal dementia, Lall stated, “We already knew mutations in a gene called C9orf72 is the most frequent cause of ALS. But, at the time we decided to do this study, not much was known about the function of this gene and how it affects cellular health and functions. If you get a mutation in a gene, it's present in every cell type. It's present in your brain cells, it's present in your liver, it's present in your spleen—everywhere. But why do specific neuronal cells in the brain degenerate and cause ALS? And what role other supporting cell types in the brain played in disease pathogenesis was still a contentious area of debate.”

“Through a number of experiments, we learned the expression of this gene is especially high in immune cells in the brain called microglial cells. This study and another paper that was published in Nature were the first to show that mutations in this gene lead to abnormal functioning of microglia cells and can contribute directly to development of ALS,” Lall described.

“Most studies in ALS are focused on mechanisms of motor neuron degeneration and not on how other cell types in the brain affect neuronal health and functions. Ultimately, this work will increase our overall understanding of the mechanisms underlying neurodegeneration. In turn, this will provide crucial knowledge toward the identification of therapeutic targets that otherwise may have been missed in model systems focused on one cell type.”

“We are trying to recapitulate what we discovered in the laboratory mice in induced pluripotent stem cells, known as “iPSC” cells,” Lall explained. “These are human stem cells created in the lab from a person's blood or skin cells and can be differentiated into any cell type in the body. That's what I'm currently working on with colleagues in Dr. Clive Svendsen’s lab. We use these cells to derive different brain cell types to understand how mutations in ALS-causing genes affect normal functioning of these cells. We culture all the disease-relevant cell types in a 3D system to mimic brain architecture and complexity.”

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