Delineating the relationship between amyotrophic lateral sclerosis and frontotemporal dementia: Sequence and structure-based predictions

Abstract

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are related neurodegenerative disorders which are characterized by a rapid decline in cognitive and motor functions, and short survival. Both syndromes may be present within the same family or even in the same person. The genetic findings for both diseases also support the existence of a continuum, with mutations in the same genes being found in patients with ALS, FTD or FTD/ALS. Little is known about the molecular mechanisms underlying the differences in mutations of the same protein causing either ALS or FTD. Here, we shed light on 348 ALS and FTD missense mutations in 14 genes focusing on genic intolerance and protein stability based on available 3D structures. Using EvoTol, we prioritized the disease-causing genes and their domain. The most intolerant genes predicted by EvoTol are SQSTM1 and OPTN which are involved in protein homeostasis. Further, using ENCoM (Elastic Network Contact Model) that predicts stability based on vibrational entropy, we predicted that most of the missense mutations with destabilizing energies are in the structural regions that control the protein-protein interaction, and only a few mutations affect protein folding. We found a trend that energy changes are higher for ALS compared to FTD mutations. The stability of the ALS mutants correlated well with the duration of disease progression as compared to FTD-ALS mutants. This study provides a comprehensive understanding of the mechanism of ALS and illustrates the significance of structure-energy based studies in differentiating ALS and FTD mutations.

Keywords: Amyotrophic lateral sclerosis; Frontotemporal dementia; Gene intolerance; Mutation; Protein stability.