Dominant negative mechanism of
            <i>Presenilin-1</i>
            mutations in FAD

Watanabe, Hirotaka; Shen, Jie

doi:10.1073/pnas.1717180114

Cited by 20 publications

(13 citation statements)

References 20 publications

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“…Interestingly, it has been proposed recently that only amyloid hypothesis cannot account for the occurrence and progression of AD. According this alternative hypothesis, mutations in Presenilin leading to AD/FAD should rather be considered as loss of function dominant negative mutations rather than gain of function mutations as significant number of these mutations severely impair the functioning of Gamma secretase instead of only increasing Aβ42 production (Kelleher and Shen, 2017;Sun et al, 2017;Watanabe and Shen, 2017). This later hypothesis is in conformity with our findings.…”

Section: Discussionsupporting

confidence: 87%

Evolutionary History of Alzheimer Disease-Causing Protein Family Presenilins with Pathological Implications

2020

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Presenilin 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 noncatalytic 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.

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Section: Discussionsupporting

confidence: 87%

Evolutionary History of Alzheimer Disease-Causing Protein Family Presenilins with Pathological Implications

2020

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“…The difference in APP processing in iPSC-derived human neurons might result from the usage of different iPSC lines or neuronal differentiation protocols between the other study and ours. Alternatively, ΔE9-mutant PS1/γ-secretase could confer a putative dominant-negative effect on γ-secretase bearing wild-type PS1/PS2 (Watanabe and Shen, 2017).…”

Section: Discussionmentioning

confidence: 99%

Flexible and Accurate Substrate Processing with Distinct Presenilin/γ-Secretases in Human Cortical Neurons

Watanabe

Imaizumi

Cai

et al. 2021

eNeuro

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Mutations in the presenilin genes (PS1, PS2) have been linked to the majority of familial Alzheimer's disease (AD). Although great efforts have been made to investigate pathogenic PS mutations, which ultimately cause an increase in the toxic form of β-amyloid (Aβ), the intrinsic physiological functions of PS in human neurons remain to be determined. In this study, to investigate the physiological roles of PS in human neurons, we generated PS1 conditional knockout induced pluripotent stem cells (iPSCs), in which PS1 can be selectively abrogated under Cre transduction with or without additional PS2 knockout. We showed that iPSC-derived neural progenitor cells do not confer a maintenance ability in the absence of both PS1 and PS2, showing the essential role of PS in Notch signaling. We then generated PS-null human cortical neurons, where PS1 was intact until full neuronal differentiation occurred. Aβ40 production was reduced exclusively in human PS1/PS2-null neurons along with a concomitant accumulation of APP-CTFs, whereas Aβ42 was decreased in neurons devoid of PS2. Unlike previous studies in mice, in which APP cleavage is largely attributable to PS1, γ-secretase activity seemed to be comparable between PS1 and PS2. In contrast, cleavage of another substrate, N-cadherin, was impaired only in neurons devoid of PS1. Moreover, PS2/γ-secretase exists largely in late endosomes/lysosomes, as measured by specific antibody against the γ-secretase complex, in which Aβ42 species are supposedly produced. Using this novel stem cell-based platform, we assessed important physiological PS1/PS2 functions in mature human neurons, the dysfunction of which could underlie AD pathogenesis. Significance Statement Presenilins are crucial catalytic subunits of γ-secretase, an intramembranous protease complex, whose mutations underlie AD pathogenesis via the dysregulation of Aβ generation. The γ-secretase complex exhibits heterogeneity via the assembly of PS1 or PS2, but the correlation of γ-secretase heterogeneity with substrate processing remains to be established in human neurons. Here, using a novel iPSC-derived cellular model carrying PS1 and/or PS2 conditional knockout alleles, we uncovered the unique processing of three substrates, Notch, APP and N-cadherin, by PS1 or PS2 in human neural cell contexts. Furthermore, the intrinsic subcellular localization of γ-secretase depends on PS1 or PS2, leading to putative differences in the processing of substrates. This novel 3 platform will help ensure the correlation of γ-secretase/substrates in human neurons.

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“…Such efforts have been informative in related fields, including familial Alzheimer disease due to Presenilin 1 (PSEN1) mutations. 100 However, the broad characterization of Notch3 function across mutations first relies on the validation and optimization of assays, allowing the detection of subtle Notch3 signaling abnormalities that might be of pathophysiological relevance.…”

Section: Existing Debate and Diverging Evidencementioning

confidence: 99%

Notch3 Signaling and Aggregation as Targets for the Treatment of CADASIL and Other NOTCH3-Associated Small-Vessel Diseases

Schoemaker

Arboleda‐Velásquez

2021

The American Journal of Pathology

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Dominant negative mechanism of Presenilin-1 mutations in FAD

Cited by 20 publications

References 20 publications

Evolutionary History of Alzheimer Disease-Causing Protein Family Presenilins with Pathological Implications

Evolutionary History of Alzheimer Disease-Causing Protein Family Presenilins with Pathological Implications

Flexible and Accurate Substrate Processing with Distinct Presenilin/γ-Secretases in Human Cortical Neurons

Notch3 Signaling and Aggregation as Targets for the Treatment of CADASIL and Other NOTCH3-Associated Small-Vessel Diseases

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