Alzheimer’s Disease: The Role of Mutations in Protein Folding

Abstract

Misfolded proteins result when a protein follows the wrong folding pathway. Accumulation of misfolded proteins can cause disorders, known as amyloid diseases. Unfortunately, some of them are very common. The most prevalent one is Alzheimer’s disease. Alzheimer’s disease is a neurodegenerative disorder and the commonest form of dementia. The current study aims to assess the impact of somatic mutations in PSEN1 gene. The said mutations are the most common cause of familial Alzheimer’s disease. As protein functionality can be affected by mutations, the study of possible alterations in the tertiary structure of proteins may reveal new insights related to the relationship between mutations and protein functions. To examine the effect of mutations, the primary structures and their related mutations were retrieved from public databases. Each structure (mutated and unmutated) was predicted based on effective structure prediction methodologies. A benchmarking of the structural predictive tools was accomplished. Comparative analyses of mutated and unmutated proteins were performed based on classic bioinformatics methods (TM-Score, RMSD, etc.) as well as on established shape-based descriptors retrieved from object recognition methodologies. Unsupervised methodologies were applied to the structures, in order to identify groups of mutation with similar mutational impact. Our results provide an essential knowledge toward protein’s functionality in structure-based drug design.