The pathophysiology of ARSACS is not completely understood, but it is believed that the loss of function of sacsin protein, a chaperone protein that helps protein folding and degradation, plays a critical role in the disease progression. The accumulation of unfolded or misfolded proteins ultimately leads to degeneration of the cerebellum and other parts of the nervous system, resulting in ataxia and other neurological symptoms.
The affected protein in ARSACS is sacsin, a large protein of 4,675 amino acids. Sacsin is mainly expressed in the cerebellum, spinal cord, and peripheral nerves, and it plays a crucial role in protein quality control in these tissues. Sacsin interacts with other proteins involved in protein folding and degradation, such as HSP70, CHIP, and p97/VCP. The loss of function of sacsin disrupts protein homeostasis, leading to neuronal damage and degeneration.
In summary, ARSACS is caused by mutations in the SACS gene, leading to loss of function of the sacsin protein, which plays a critical role in protein quality control. The accumulation of unfolded or misfolded proteins leads to degeneration of the cerebellum and other parts of the nervous system, resulting in ataxia and other neurological symptoms.
SACS