Evolutionary History of Alzheimer Disease-Causing Protein Family Presenilins with Pathological Implications
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ORIGINAL ARTICLE
Evolutionary History of Alzheimer Disease‑Causing Protein Family Presenilins with Pathological Implications Ammad Aslam Khan1,2 · Raja Hashim Ali3,4 · Bushra Mirza5 Received: 9 February 2019 / Accepted: 22 September 2020 / Published online: 1 October 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Presenilin proteins make the catalytic component of γ-secretase, a multiprotein transmembrane protease, and are type II transmembrane proteins. Amyloid protein, Notch, and beta catenin are among more than 90 substrates of Presenilins. Mutations in Presenilins lead to defects in proteolytic cleavage of its substrate resulting in some of the most devastating pathological conditions including Alzheimer disease (AD), developmental disorders, and cancer. In addition to catalytic roles, Presenilin protein is also shown to be involved in many non-catalytic roles, i.e., calcium homeostasis, regulation of autophagy, and protein trafficking, etc. These proteolytic proteins are highly conserved and are present in almost all the major eukaryotic groups. Studies, performed on a wide variety of organisms ranging from human to unicellular dictyostelium, have shown the important catalytic and non-catalytic roles of Presenilins. In this study, we infer the evolutionary patterns and history of Presenilins as well as of other γ-secretase proteins. We show that Presenilins are the most ancient of the γ-secretase proteins and that Presenilins may have their origin in the last common ancestor (LCA) of Eukaryotes. We also demonstrate that Presenilin proteins generally lack diversifying selection during the course of their evolution. Through evolutionary trace analysis, we show that Presenilin protein sites that undergo mutations in Familial Alzheimer disease, are highly conserved in metazoans. Finally, we discuss the evolutionary, physiological, and pathological implications of our findings and propose that the evolutionary profile of Presenilins supports the loss of function hypothesis of AD pathogenesis. Keywords γ-Secretase · Presenilin · Alzheimer disease · Amyloid-beta · Endoproteolysis · Protein evolution Handling editor: Joana Projecto-Garcia. Ammad Aslam Khan and Raja Hashim Ali have contributed equally to this work. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00239-020-09966-w) contains supplementary material, which is available to authorized users. * Ammad Aslam Khan [email protected]; [email protected] 1
Department of Bioinformatics and Computational Biology, Virtual University, Lahore 547 92, Pakistan
2
Department of Biochemistry, Barrett Hodgson University, Korangi Creek, Karachi 749 00, Pakistan
3
Machine Intelligence Group (MInG Lab), Faculty of Computer Science And Engg., Ghulam Ishaq Khan Institute of Engg. Sciences and Technology, Topi 236 40, Pakistan
4
Department of Evolutionary Biology, Evolutionary Biology Center, Uppsala University, 751 05 Uppsala, Sweden
5
Department of Animal Sciences,
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