Scientists have discovered variation within different areas of the brain and spinal cord of people living with ALS — some areas show greater degeneration while others are unaffected. With a $125,000 project grant from the ALS Canada Research Program in 2018, Dr. Janice Robertson and Dr. Paul McKeever, a postdoctoral fellow in her lab, will be among the first to apply two powerful new technologies to ALS research to investigate why these differences in the brain and spinal cord can occur. Insights from this crucial work will lead to a better understanding of the disease process, potentially uncovering new approaches to treat ALS.

Variation in the most common genetic form of ALS

Mutations in the C9ORF72 gene are the most common cause of familial ALS and also about 7% of sporadic ALS cases. The mutations are repeated sections of DNA. Hundreds and sometimes thousands of the repeats have been found in people with the disease. “But the number of repeats varies in different cell types in the brain and spinal cord,” said Dr. Robertson, The James Hunter Family Chair in ALS Research at the Tanz Centre for Neurodegenerative Diseases at the University of Toronto. “We need to find out if these differences explain why motor neurons in the brain and spinal cord degenerate while other types of neurons do not.”

New scientific technologies

Traditional research methods have involved either examining one cell at a time under a microscope or lumping whole tissues with thousands of different cells mixed together. These approaches have led to some important insights about neurodegenerative disease processes but have not allowed researchers to measure the genetic changes that either predispose individual cells to ALS or protect them from the disease.

Left to right: Dr. Janice Robertson, Dr. Paul McKeever
Left to right: Dr. Janice Robertson, Dr. Paul McKeever

Dr. McKeever conceived the current project that takes advantage of two breakthrough advancements in how individual cells are analyzed, called sNuc-Seq and ATAC-Seq. These new technologies will allow the researchers to examine the nuclei of about six thousand single-cells at a time. “Here we will learn how mutations in C9ORF72 lead to changes in gene regulation and expression in individual brain cells” said Dr. McKeever.

They will analyze cells from the spinal cord, two areas of the brain affected by ALS — the motor cortex and the frontal cortex — as well as tissue from the area of the brain that processes visual input called the occipital cortex, usually one of the last regions affected by ALS. They will compare findings from these areas for people with C9ORF72-ALS, sporadic ALS and no ALS.

Drs. Robertson and McKeever hypothesize that these new technologies will reveal the reasons why certain cells degenerate in ALS whereas others do not. Examining these cellular processes at such a deep level has never been done before in ALS research.

The tissue used in the project is donated generously by deceased ALS patients through the ALS Clinic at the Sunnybrook Health Sciences Centre. “We are incredibly grateful to those living with ALS and their families who have made this ground-breaking research possible,” Dr. Robertson said.

The power of collaboration

In addition to their collaboration with Dr. Lorne Zinman, Director of the ALS clinic at Sunnybrook Health Sciences Centre, Dr. McKeever identified other experts from the University Health Network and the University of Toronto who are collaborating on this project.

Dr. Troy Ketela’s functional genomics team at the Princess Margaret Genomic Centre will contribute their extensive experience with sNuc-Seq methods. Dr. Gary Bader’s computational network biology lab at the Terence Donnelly Centre for Cellular and Biomolecular Research will develop the bioinformatics tools to analyze the billions of sequences generated. Dr. Ekaterina Rogaeva, a research colleague of Drs. Robertson and McKeever at the Tanz Center for Neurodegenerative Diseases, will examine the changes in DNA that have been caused by environmental impacts over time without changing the underlying structure of the DNA. Dr. Rita Sattler, at the Barrow Neurological Institute in Phoenix, Arizona, will investigate these environmental impacts further using neurons derived from human stem cells.

“I’m excited that all of these multidisciplinary teams are coming together to make this work,” Dr. Robertson said. “Learning about the variations in ALS in different cell types will revolutionize our understanding of the disease process, allowing us to devise new approaches to treat the disease in the future.”

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 panelists 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