Dissecting the role of disease-associated microglia in ARSACS disease progression

Autosomal recessive spastic ataxia of Charlevoix–Saguenay (ARSACS) is a rare inherited neurological disorder that begins in childhood and causes progressive problems with balance, coordination, and muscle control. ARSACS is caused by mutations in the SACS gene, which produces a large protein called sacsin. Sacsin is especially important in the cerebellum, the part of the brain responsible for coordinating movement. In ARSACS, the nerve cells that carry out this function—called Purkinje cells (PCs)—are among the first to become damaged, and their loss plays a major role in the symptoms of the disease. Our previous research has shown that loss of sacsin disrupts the cytoskeleton of these nerve cells, affecting how they move essential components such as mitochondria. These defects eventually lead to PC cell stress and degeneration. We have now discovered that ARSACS also triggers a strong immune response in the brain. Microglia, the brain’s resident immune cells, shift from a resting state into a highly active form known as disease-associated microglia (DAM). DAM are known to influence the progression of other neurological conditions, but their role in ARSACS is not yet understood. The goal of this project is to determine whether this immune reaction contributes to nerve cell damage or instead acts as a protective response. Aim 1: Map when these activated microglia appear in the ARSACS brain and determine whether they are concentrated in areas where PCs are beginning to degenerate. Aim 2: Experimentally adjust microglial activity in the mouse model of ARSACS to find out whether enhancing or reducing this response affects nerve cell survival. By revealing how the brain’s immune system influences the progression of ARSACS, this research may uncover new targets for treatment and help pave the way toward effective therapies for this currently incurable childhood disorder.