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Proceedings of the National Academy of... Feb 2011Presenilin mutations are the main cause of familial Alzheimer's disease (FAD). Presenilins also play a key role in Ca(2+) homeostasis, and their FAD-linked mutants...
Presenilin mutations are the main cause of familial Alzheimer's disease (FAD). Presenilins also play a key role in Ca(2+) homeostasis, and their FAD-linked mutants affect cellular Ca(2+) handling in several ways. We previously have demonstrated that FAD-linked presenilin 2 (PS2) mutants decrease the Ca(2+) content of the endoplasmic reticulum (ER) by inhibiting sarcoendoplasmic reticulum Ca(2+)-ATPase (SERCA) activity and increasing ER Ca(2+) leak. Here we focus on the effect of presenilins on mitochondrial Ca(2+) dynamics. By using genetically encoded Ca(2+) indicators specifically targeted to mitochondria (aequorin- and GFP-based probes) in SH-SY5Y cells and primary neuronal cultures, we show that overexpression or down-regulation of PS2, but not of presenilin 1 (PS1), modulates the Ca(2+) shuttling between ER and mitochondria, with its FAD mutants strongly favoring Ca(2+) transfer between the two organelles. This effect is not caused by a direct PS2 action on mitochondrial Ca(2+)-uptake machinery but rather by an increased physical interaction between ER and mitochondria that augments the frequency of Ca(2+) hot spots generated at the cytoplasmic surface of the outer mitochondrial membrane upon stimulation. This PS2 function adds further complexity to the multifaceted nature of presenilins and to their physiological role within the cell. We also discuss the importance of this additional effect of FAD-linked PS2 mutants for the understanding of FAD pathogenesis.
Topics: Aequorin; Blotting, Western; Calcium Signaling; Cell Line, Tumor; Endoplasmic Reticulum; Fluorescence Resonance Energy Transfer; Humans; Microscopy, Fluorescence; Mitochondria; Mutation; Presenilin-2; RNA, Small Interfering
PubMed: 21285369
DOI: 10.1073/pnas.1100735108 -
The Journal of Biological Chemistry Nov 2000Presenilins are integral membrane protein involved in the production of amyloid beta-protein. Mutations of the presenilin-1 and -2 gene are associated with familial...
Presenilins are integral membrane protein involved in the production of amyloid beta-protein. Mutations of the presenilin-1 and -2 gene are associated with familial Alzheimer's disease and are thought to alter gamma-secretase cleavage of the beta-amyloid precursor protein, leading to increased production of longer and more amyloidogenic forms of A beta, the 4-kDa beta-peptide. Here, we show that radiolabeled gamma-secretase inhibitors bind to mammalian cell membranes, and a benzophenone analog specifically photocross-links three major membrane polypeptides. A positive correlation is observed among these compounds for inhibition of cellular A beta formation, inhibition of membrane binding and cross-linking. Immunological techniques establish N- and C-terminal fragments of presenilin-1 as specifically cross-linked polypeptides. Furthermore, binding of gamma-secretase inhibitors to embryonic membranes derived from presenilin-1 knockout embryos is reduced in a gene dose-dependent manner. In addition, C-terminal fragments of presenilin-2 are specifically cross-linked. Taken together, these results indicate that potent and selective gamma-secretase inhibitors block A beta formation by binding to presenilin-1 and -2.
Topics: Amyloid Precursor Protein Secretases; Cell Membrane; Endopeptidases; Enzyme Inhibitors; Membrane Proteins; Precipitin Tests; Presenilin-1; Presenilin-2; Substrate Specificity
PubMed: 10915801
DOI: 10.1074/jbc.M005430200 -
Postepy Higieny I Medycyny... Jun 2012The research conducted on animal models of Alzheimer's disease (AD) has provided valuable information about the pathogenesis of this disease and associated behavioral... (Review)
Review
The research conducted on animal models of Alzheimer's disease (AD) has provided valuable information about the pathogenesis of this disease and associated behavioral and cognitive deficits as well as the disease-associated anatomical and histopathological lesions of the brain. Transgenic technologies have enabled the creation of animal models based on mutations in APP, MAPT, presenilin genes, tau protein and apoE. Due to economic reasons studies are mainly conducted on mice. Their brain tissue, depending on the mutation, is characterized by histopathological changes, such as the presence of amyloid plaques, tau protein deposits and dystrophic neurites, gliosis, hippocampal atrophy and amyloid accumulation in vessels. Animal cognitive impairment and behavior, which can be demonstrated in behavioral tests, primarily relate to the working and reference memory, alternation and anxiety. Unfortunately, despite the various modifications specific to AD in the genome of animals, scientists have failed to create an animal model characterized by all the pathological changes that can occur in Alzheimer's disease. Nevertheless, the role of transgenic animals is undeniable, both in research on AD neuropathology and for testing new therapies, such as immunotherapy. Despite the occurrence of abundant Alzheimer's disease mice models this article is dedicated to selected models with mutations in the APP, MAPT and presenilin genes and their application for behavioral studies.
Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Apolipoproteins E; Brain; Disease Models, Animal; Gliosis; Mice; Mice, Transgenic; Mutation; Plaque, Amyloid; Presenilins; tau Proteins
PubMed: 22922141
DOI: 10.5604/17322693.1001098 -
Brain Research Dec 2012Presenilins are necessary for calcium homeostasis and also for efficient proteolysis through the autophagy/lysosome system. Presenilin regulates both endoplasmic...
Presenilins are necessary for calcium homeostasis and also for efficient proteolysis through the autophagy/lysosome system. Presenilin regulates both endoplasmic reticulum calcium stores and autophagic proteolysis in a γ-secretase independent fashion. The endo-lysosome system can also act as a calcium store, with calcium efflux channels being recently identified as two-pore channels 1 and 2. Here we investigated lysosomal calcium content and the channels that mediate calcium release from these acidic stores in presenilin knockout cells. We report that presenilin loss leads to a lower total lysosomal calcium store despite the buildup of lysosomes found in these cells. Additionally, we find alterations in two-pore calcium channel protein expression, with loss of presenilin preventing the formation of a high molecular weight species of TPC1 and TPC2. Finally, we find that treatments that disturb lysosomal calcium release lead to a reduction in autophagy function yet lysosomal inhibitors do not alter two-pore calcium channel expression. These data indicate that alterations in lysosomal calcium in the absence of presenilins might be leading to disruptions in autophagy.
Topics: Animals; Autophagy; Calcium; Calcium Channels; Cells, Cultured; Fibroblasts; Gene Expression; Green Fluorescent Proteins; Lysosomes; Mice; Mice, Knockout; Presenilin-1; Presenilin-2
PubMed: 23103503
DOI: 10.1016/j.brainres.2012.10.036 -
Cells Aug 2021Presenilin 2 (PS2), one of the three proteins in which mutations are linked to familial Alzheimer's disease (FAD), exerts different functions within the cell...
Presenilin 2 (PS2), one of the three proteins in which mutations are linked to familial Alzheimer's disease (FAD), exerts different functions within the cell independently of being part of the γ-secretase complex, thus unrelated to toxic amyloid peptide formation. In particular, its enrichment in endoplasmic reticulum (ER) membrane domains close to mitochondria (i.e., mitochondria-associated membranes, MAM) enables PS2 to modulate multiple processes taking place on these signaling hubs, such as Ca handling and lipid synthesis. Importantly, upregulated MAM function appears to be critical in AD pathogenesis. We previously showed that FAD-PS2 mutants reinforce ER-mitochondria tethering, by interfering with the activity of mitofusin 2, favoring their Ca crosstalk. Here, we deepened the molecular mechanism underlying PS2 activity on ER-mitochondria tethering, identifying its protein loop as an essential domain to mediate the reinforced ER-mitochondria connection in FAD-PS2 models. Moreover, we introduced a novel tool, the PS2 loop domain targeted to the outer mitochondrial membrane, Mit-PS2-LOOP, that is able to counteract the activity of FAD-PS2 on organelle tethering, which possibly helps in recovering the FAD-PS2-associated cellular alterations linked to an increased organelle coupling.
Topics: Alzheimer Disease; Calcium; Cell Line, Tumor; Cytosol; Endoplasmic Reticulum; Fibroblasts; Humans; Lipid Droplets; Mitochondria; Mutagenesis; Presenilin-1; Presenilin-2; Protein Domains
PubMed: 34440738
DOI: 10.3390/cells10081968 -
Molecular Psychiatry Jan 2004
Review
Topics: Alzheimer Disease; Amyloid Precursor Protein Secretases; Animals; Aspartic Acid Endopeptidases; Endopeptidases; Humans; Membrane Proteins; Presenilin-1; Presenilin-2
PubMed: 14581930
DOI: 10.1038/sj.mp.4001438 -
Cells Mar 2019The presenilin (PS) proteins exert a crucial role in the pathogenesis of Alzheimer disease (AD) by mediating the intramembranous cleavage of amyloid precursor protein... (Review)
Review
The presenilin (PS) proteins exert a crucial role in the pathogenesis of Alzheimer disease (AD) by mediating the intramembranous cleavage of amyloid precursor protein (APP) and the generation of amyloid β-protein (Aβ). The two homologous proteins PS1 and PS2 represent the catalytic subunits of distinct γ-secretase complexes that mediate a variety of cellular processes, including membrane protein metabolism, signal transduction, and cell differentiation. While the intramembrane cleavage of select proteins by γ-secretase is critical in the regulation of intracellular signaling pathways, the plethora of identified protein substrates could also indicate an important role of these enzyme complexes in membrane protein homeostasis. In line with this notion, PS proteins and/or γ-secretase has also been implicated in autophagy, a fundamental process for the maintenance of cellular functions and homeostasis. Dysfunction in the clearance of proteins in the lysosome and during autophagy has been shown to contribute to neurodegeneration. This review summarizes the recent knowledge about the role of PS proteins and γ-secretase in membrane protein metabolism and trafficking, and the functional relation to lysosomal activity and autophagy.
Topics: Amyloid Precursor Protein Secretases; Animals; Autophagy; Cell Membrane; Humans; Membrane Proteins; Presenilins; Proteostasis
PubMed: 30823664
DOI: 10.3390/cells8030209 -
The Journal of Clinical Investigation Feb 2023
Topics: Mice; Animals; Presenilins; Calcium; Signal Transduction; Neurons; MicroRNAs; Presenilin-1
PubMed: 36787258
DOI: 10.1172/JCI169139 -
The Journal of Clinical Investigation Feb 2023
Topics: Mice; Animals; Presenilins; Calcium; Signal Transduction; Neurons; MicroRNAs; Presenilin-1
PubMed: 36719380
DOI: 10.1172/JCI168441 -
Nature Apr 1999Presenilins are membrane proteins with multiple transmembrane domains that are thought to contribute to the development of Alzheimer's disease by affecting the...
Presenilins are membrane proteins with multiple transmembrane domains that are thought to contribute to the development of Alzheimer's disease by affecting the processing of beta-amyloid precursor protein. Presenilins also facilitate the activity of transmembrane receptors of the LIN-12/Notch family. After ligand-induced processing, the intracellular domain of LIN-12/Notch can enter the nucleus and participate in the transcriptional control of downstream target genes. Here we show that null mutations in the Drosophila Presenilin gene abolish Notch signal transduction and prevent its intracellular domain from entering the nucleus. Furthermore, we provide evidence that presenilin is required for the proteolytic release of the intracellular domain from the membrane following activation of Notch by ligand.
Topics: Animals; Cell Nucleus; Drosophila; Drosophila Proteins; Female; Male; Membrane Proteins; Mutation; Presenilins; Receptors, Notch; Signal Transduction; Trans-Activators
PubMed: 10206646
DOI: 10.1038/19091