Q&A With ALS Researcher Deepti Lall, PhD

Newswise — LOS ANGELES (May 17, 2022) -- 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.

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

In an interview with the Cedars-Sinai Newsroom, Lall explains why she thinks looking beyond neurons may help lead to a cure. 

Newsroom: First, how did you become interested in studying the brain and neurological disorders like ALS?
Lall: Since my undergraduate studies, I have been intrigued by the mystery and the complexity of the brain. During my graduate studies, I realized I wanted to spend my life learning more about the functioning of the brain and how normal brain functions go haywire in neurological disorders. There is still so little that we know about these diseases, and the fact we have so much to discover excites me to continue with my research. As a scientist, I am passionate about making a difference in the lives of people suffering from these devastating disorders. Working in neuroscience research helps me understand the fundamental biology of neurodegenerative disorders, such as ALS, and share the responsibility of helping patients.

Newsroom: You are the lead author of a study published in 2021 that reported the brain's immune cells may play a role in ALS and frontotemporal dementia. Could you describe what exactly you discovered?
Lall: 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.

Newsroom: What might these findings mean for potential treatments?
Lall: 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.

Newsroom: What are you working on now?
Lall: We are trying to recapitulate what we discovered in the laboratory mice in induced pluripotent stem cells, known as “iPSC” cells. 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.

Newsroom: What gives you optimism when it comes to ALS treatments?
Lall: A lot of progress has been made in the past decade in uncovering disease mechanisms in ALS. In the past, a lot of focus had been put on understanding neuron-specific disease mechanisms, as these are the cells that degenerate in ALS. In recent years, more focus has been on understanding the brain as a whole and how the other cell types play a role in disease pathogenesis.

What gives me optimism is that more and more people are taking an integrative approach to understanding the disease pathogenesis. Dr. Svendsen, for example, is studying how another glial cell type in the brain, called astrocytes, can be therapeutically targeted to support and improve neuronal health and survival. That makes me optimistic about the various tracks scientists can take to develop novel therapeutic targets. Also, the Accelerating Access to Critical Therapies for ALS Act signed by President Biden this year opens up a new level of funding and opportunities for scientists to take the road less traveled to unravel novel disease mechanisms that can be therapeutically targeted.

Read more on the Cedars-Sinai Blog: ALS Patient Matt Ashley Shares Learnings From ‘Heartbreaking’ Disease