aspartoacylase

Aspartoacylase is an enzyme that catalyzes the hydrolysis of N-acetyl-L-aspartate (NAA) into L-aspartate and acetate. In humans it is encoded by the ASPA gene. The enzyme is primarily expressed in the brain, especially in oligodendrocytes and regions rich in myelin, where it participates in NAA metabolism and contributes to the maintenance of neuronal and white matter function.

Biochemical role and function: By removing the acetyl group from NAA, aspartoacylase helps regulate brain levels of NAA and provides acetate that can be used for lipid synthesis in oligodendrocytes. The exact physiological roles of NAA and aspartoacylase remain an area of active research, but disruption of this pathway is linked to myelin pathology and altered osmoregulation in the brain.

Genetics and disease: Mutations in ASPA cause Canavan disease, an autosomal recessive neurodegenerative disorder. Canavan disease typically presents in infancy with hypotonia, rapid motor and cognitive decline, and macrocephaly. Pathology shows spongiform degeneration of white matter, a consequence of deficient aspartoacylase activity and elevated brain NAA levels.

Diagnosis and incidence: Canavan disease is diagnosed through clinical assessment, elevated NAA detected by magnetic resonance spectroscopy, and confirmation by ASPA genetic testing. The condition is rare but has higher reported frequency in certain populations, including individuals of Ashkenazi Jewish descent due to founder mutations.

Treatment and research: There is no cure, and management is supportive. Research efforts focus on restoring aspartoacylase activity, including gene therapy approaches and other strategies to modulate NAA metabolism, with ongoing preclinical and early clinical investigations.