Canavan's Disease Essay

Canavan’s disease is one of the most common and fatal progressive cerebellar degenerative disorder affecting the white matter of the brain which is caused due to the enzyme aspartoacylase. 1 Aspartoacylase (ASPA gene) promotes the deacetylation of N-acetylaspartic acid (NAA) to produce acetate and L-aspartate which is the only brain enzyme that has been shown to effectively metabolize NAA. 2 NAA metabolism plays a major role in the formation of myelin lipids. Oligodendrocytes present in the brain are enriched with ASPA and its deficiency results in increased levels of its substrate (NAA) causing brain edema and dysmyelination. 3 The ASPA deficiency leads to accumulation of NAA in brain and it is excreted in urine of patients. 4 Mutations in the ASPA gene hinder the activity of aspartoacylase. It prevents the normal breakdown of NAA. Increasing quantity of NAA also leads to
The glutamate residue, which is negatively charged, present at 285th position is essential to maintain the aspartoacylase function and also support the catalytic function and is located near the enzyme active site. 15-18 Computational analysis of mutation E285A could bring new insights into reasons underlying pathogenesis of the disease. 19, 20 On the whole, this study would help us understanding the structural and functional defects of the enzyme and disease causing mutation. We have analyzed native and mutant structures to understand the deleterious effects through conformation sampling approach which is an alternate to classical molecular dynamics. The study also gains interest since there are no prior molecular dynamics analyses for the disease. Moreover, this work could direct the implementation of nanomechanics to understand the misfolding nature of protein by the deleterious effect of missense