In Canada, between 3,000 and 4,000 people are living with amyotrophic lateral sclerosis (ALS), a disease that remains incurable. ALS is best known for the degeneration of motor neurons, which are responsible for controlling movement. Their progressive loss, particularly in the motor cortex and spinal cord, leads to rapid paralysis, with a life expectancy of 2 to 5 years after diagnosis.
This serious neurodegenerative disease causes a gradual loss of muscle control, typically leading to paralysis within a few years. Until now, research has primarily focused on brain regions directly involved in movement. However, a new study led by Professor Kessen Patten , at the Institut national de la recherche scientifique (INRS) and holder of the Anna Sforza Djoukhadjian Research Chair in Amyotrophic Lateral Sclerosis , proposes a major shift in perspective: the disease may begin elsewhere in the brain, and well before the first visible symptoms appear.
Published in the journal Brain , the study , obtained from zebrafish models and human clinical samples, sheds new light on early brain changes associated with ALS. These findings provide new insight into the disease and may help inform future efforts toward earlier diagnosis and therapeutic development, as nearly 1,000 new cases are diagnosed each year in Canada.
Rather than focusing solely on motor regions, researchers turned their attention to the cerebellum, a brain region associated with balance and coordination, but long underestimated in ALS.
In the most common genetic form of the disease (linked to the C9orf72 gene) in zebrafish, they observed early cerebellar atrophy, characterized by the loss of two essential types of neurons: Purkinje cells and granule cells, well before the onset of motor symptoms.
Zebrafish are widely used in biomedical research because they share many genetic and cellular mechanisms with humans, making them a valuable model for studying neurodegenerative diseases such as ALS.
“Our results show that ALS is not limited to motor regions of the brain. Significant changes occur elsewhere, long before symptoms appear, which profoundly changes our understanding of the disease.”
— Dr. Kessen Patten, Professor of Genetics and Neurodegenerative Diseases at INRS and lead author of the study.
To understand this phenomenon, the team used an advanced technology that allows researchers to analyze gene activity in individual cells. This approach led to the identification of a key issue: decreased activity of the paics gene, which produces an enzyme essential for the synthesis of purines, molecules required to build and repair DNA.
Without these molecules, cells become unable to repair the DNA damage that naturally occurs. This damage accumulates progressively, leading to the failure of repair mechanisms and, ultimately, to neuron death.
When paics gene activity decreases, DNA damage accumulates and cellular repair systems eventually fail, leading to cell degeneration.
“We were able to establish a direct link between a defect in the production of purines and the accumulation of DNA damage in brain cells, which helps us better understand the origin of their degeneration.”
— Jaskaran Singh , Doctoral student at INRS and first author of the study
One of the most promising findings is that this mechanism may be reversible.
In an experimental model, researchers were able to restore paics gene activity. As a result, DNA damage decreased, neurons survived, and disease progression was halted at the cellular level.
For people living with ALS and their families, these findings represent an important step forward. By showing that restoring paics function can reduce DNA damage and help protect neurons in experimental models, the study points to a promising pathway that could be explored in future therapeutic research. While further studies are needed, this work contributes to ongoing efforts to better understand the disease and its progression.
About the study
Jaskaran Singh, Léa Lescouzères, Charlotte Zaouter, Mathilde Chaineau, Ghazal Haghi, Thomas M Durcan, Shunmoogum A Patten, PAICS mediates DNA damage and cerebellar neuronal loss in C9orf72 amyotrophic lateral sclerosis, Brain, 2026;, awag092, https://doi.org/10.1093/brain/awag092
This work was made possible through funding from Brain Canada, Cermo-FC, the Armand-Frappier Foundation, the Fonds de recherche du Québec – Santé, the Anna Sforza Djoukhadjian Research Chair in Amyotrophic Lateral Sclerosis of the Armand-Frappier Foundation, the Natural Sciences and Engineering Research Council of Canada, and the Canadian Institutes of Health Research.
About INRS
INRS is an academic institution dedicated exclusively to graduate research and training in strategic sectors in Quebec. Since 1969, as per its mission, it has actively contributed to Quebec’s economic, social, and cultural development. INRS ranks first in Quebec in research intensity. It is made up of five interdisciplinary research and training centres located in Quebec City, Montreal, Laval, and Varennes, and Charlevoix, which focus their efforts on strategic sectors: water, earth, and environment ( Eau Terre Environnement Research Centre ); energy, materials, and telecommunications ( Énergie Matériaux Télécommunications Research Centre ); urbanization, culture, and society ( Urbanisation Culture Société Research Centre ); and health and biotechnology ( Armand-Frappier Santé Biotechnologie Research Centre ), and Ruralités durables (a center currently under development). Its community includes nearly 1,500 members, including students, postdoctoral fellows, faculty members, and staff.
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PAICS mediates DNA damage and cerebellar neuronal loss in C9orf72 amyotrophic lateral sclerosis
11-Mar-2026