Bioinformatics Analysis of Amyotrophic Lateral Sclerosis Associated Amino Acid Mutations

Amino acid mutations in several proteins are reported to cause amyotrophic lateral sclerosis (ALS) , a devastating neurodegenerative disease with uncertain etiology. To study the genotype-phenotype relationship in ALS and to improve the understanding of the molecular mechanism of this disease, all the known ALS associated amino acid mutations happened at five enzymes are collected and analyzed with bioinformatics tools and methods. Our results demonstrate that the 139 mutations in the 5 enzymes have diverse effects on structure and function of the studied proteins, indicating that ALS is a complex disease. The ALS associated amino acid mutations are shown to affect the structural stability, propensity for aggregation, electrostatic properties, etc. Most of the mutations are located at conserved sites, which are usually essential in determining protein structure and function. A large proportion of the missense mutations was found increase the protein aggregates and decrease the protein stability. Our analyses systematically provided the putative effects of all known mutations in five studied proteins, allowing further verify the hypothesis of ALS pathogenesis.