Written by Dr. Ambika Tewari Edited by Larissa Nitschke
Tipping the balance of the protein Sacsin alters outcomes in a mouse model of ARSACS
There are many different types of ataxia, each with a unique cause. For several ataxias, the mutated gene that causes the disorder has been identified. This is a great achievement that we owe to recent advancements in genome sequencing. Knowing the gene that is altered in a disorder provides researchers with a solid foundation to understand the mechanisms underlying the disease. In the neurodegenerative disorder Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), this alteration occurs in the SACS gene. Currently, over 170 different SACS gene mutations have been identified in human patients. Because each gene is equipped with a specific set of instructions to make a protein, each mutation can cause a change in these instructions. This usually results in the production of very little sacsin protein – or no protein at all. In several disorders, it has been shown that maintaining optimal levels of a variety of proteins is crucial to the proper functioning of the nervous system.
In 2015, a group of researchers wanted to understand why the loss of the protein sacsin produced certain symptoms in ARSACS patients. To study this, they removed the entire SACS gene from a mouse (known as the Sacs-/- line), which meant that these mice made no sacsin protein. Mice with only one copy of this mutation (Sacs+/-) could produce up to 50% of the protein. In this same study, the researchers also wanted to make a more disease-relevant mouse model, so they made a mouse with a mutation known as “R272C.” R272C was a SACS gene mutation that was initially identified in a patient with ARSACS. Mice with two copies of the mutated gene (SacsR262C/R262C) had sacsin levels reduced to 21%, whereas mice with one copy (SacsR262C/+) had 65% of sacsin levels. Together, these mouse models provided the researchers with a group of mice that had a range of sacsin protein levels. These mice could then be used to understand how changes in the levels of sacsin affect behavior, especially in the ways that we might observe in ARSACS.
ARSACS patients have a childhood onset of ataxia that worsens over time. This is due to the loss of Purkinje cells in the cerebellum, the area of the brain that controls motor coordination. Without Purkinje cells, the cerebellum cannot properly function, resulting in the uncoordinated gait that we call “ataxia.” The researchers found that mice with less than 50% sacsin protein also displayed progressive motor abnormalities (measured using three well-established mouse coordination tests). These mice also showed degeneration of Purkinje cells, which became more apparent with increasing age. Moreover, as protein levels decreased, motor performance and Purkinje cell loss became more pronounced.