Canavan disease (CD) is a fatal neurodegenerative disorder caused by the deficiency of aspartoacylase (ASPA). ASPA catalyzes the hydrolysis of N-acetyl-L-aspartate to produce acetate for myelin lipid biosynthesis. More than seventy mutations of ASPA have been reported, and the majority of these are located remote from the active site. Several of these mutants with different clinical presentations have now been characterized. Each mutant has varying degree of diminished catalytic activity and lower stability than the native enzyme. The diminished ASPA activity observed in CD is likely a result of destabilization of the enzyme structure.  Compounds that selectively interact with ASPA mutants have been identified by molecular docking studies and a high-throughput stability assay. Optimization of these hit compounds by kinetic and structural studies could lead to development of potential pharmacological chaperones that could recover the activity of mutant enzymes and reverse the detrimental effects of CD.

Biophysical characteristics of aspartoacylase clinical mutants and a pharmacological chaperone approach for the treatment of canavan disease

245th National Meeting (2013)

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