From Damage to Renewal: Inducing Mitophagy to Reverse Mitochondrial defects in Autosomal Recessive Spastic Ataxia of Charlevoix–Saguenay (ARSACS)

ARSACS is a rare, inherited neurodegenerative disease that usually begins in childhood and causes progressive problems with balance, coordination, and movement. ARSACS is caused by mutations in a gene called SACS, which produces a protein known as Sacsin. The function of this protein is not well understood but when Sacsin is missing or not working properly, neuronal cells, especially those in the brain part that control movement, gradually die. Currently, there is no cure or treatment able to slow down or stop the disease. Research has shown that one of the main problems in ARSACS is the malfunction of mitochondria, the tiny “power plants” of our cells that produce energy in the form of ATP. In healthy cells, damaged mitochondria are regularly removed and replaced through a process called mitophagy. In ARSACS, this process does not work correctly, leading to the accumulation of defective mitochondria and excessive cellular stress, which can contribute to neuronal death. Our project aims to understand why mitophagy fails when Sacsin is lost and to test a potential new way to reactivate this vital mechanism of quality control of mitochondria. We will focus on a protein called USP14, whose inhibition has been shown by our group to stimulate mitophagy and improve mitochondrial health in neurons. By studying neurons derived from human stem cells and other cell models of ARSACS, we will explore whether inhibiting USP14 can help clear damaged mitochondria, restore energy balance, and protect from neurodegeneration in cells modelling ARSACS. By uncovering how mitochondrial quality control is disrupted in ARSACS and testing a new way to fix it, this research will provide valuable knowledge that could lead to a therapy aimed at one of the possible causes of the disease, offering new therapeutic target for patients affected by ARSACS.