AbstractPresenilin proteins are type II transmembrane proteins. They make the catalytic component of Gamma secretase, a multiportion transmembrane protease. 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, present in almost all the major eukaryotic groups. Studies on wide variety of organisms ranging from human to unicellular dictyostelium have shown the important catalytic and non-catalytic roles of Presenilins. In the current research project, we aimed to elucidate the phylogenetic history of Presenilins. We showed that Presenilins are the most ancient of the Gamma secretase proteins and might have their origin in last common eukaryotic ancestor (LCEA). We also demonstrated that these proteins have been evolving under strong purifying selection. Through evolutionary trace analysis, we showed that Presenilin protein sites which undergoes mutations in Familial Alzheimer Disease are highly conserved in metazoans. Finally, we discussed the evolutionary, physiological and pathological implication of our findings and proposed that evolutionary profile of Presenilins supports the loss of function hypothesis of AD pathogenesis.
The Alzheimer Disease-Causing Presenilin-1 L435F Mutation Causes Increased Production of Soluble Aβ43 Species in Patient-Derived iPSC-Neurons, Closely Mimicking Matched Patient Brain Tissue
