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Nihon Rinsho. Japanese Journal of... Oct 2011
Topics: Alzheimer Disease; Amyloid Precursor Protein Secretases; Humans; Presenilins
PubMed: 22787762
DOI: No ID Found -
International Journal of Molecular... May 2021Perinatal asphyxia is mainly a brain disease leading to the development of neurodegeneration, in which a number of peripheral lesions have been identified; however,...
Perinatal asphyxia is mainly a brain disease leading to the development of neurodegeneration, in which a number of peripheral lesions have been identified; however, little is known about the expression of key genes involved in amyloid production by peripheral cells, such as lymphocytes, during the development of hypoxic-ischemic encephalopathy. We analyzed the gene expression of the , , and and by RT-PCR in the lymphocytes of post-asphyxia and control neonates. In all examined periods after asphyxia, decreased expression of the genes of the , and was noted in lymphocytes. Conversely, expression of and genes decreased on days 1-7 and 8-14 but increased after survival for more than 15 days. We believe that the expression of genes in lymphocytes could be a potential biomarker to determine the severity of the post-asphyxia neurodegeneration or to identify the underlying factors for brain neurodegeneration and get information about the time they occurred. This appears to be the first worldwide data on the role of the and genes associated with Alzheimer's disease in the dysregulation of neonatal lymphocytes after perinatal asphyxia.
Topics: Asphyxia; Case-Control Studies; Female; Gene Expression Regulation; Humans; Infant, Newborn; Lymphocytes; Male; Presenilin-1; Presenilin-2
PubMed: 34067945
DOI: 10.3390/ijms22105140 -
Ernst Schering Research Foundation... 2000
Review
Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain; Caenorhabditis elegans; Humans; Membrane Proteins; Presenilin-1; Presenilin-2; Presenilins; Receptors, Notch; Signal Transduction; Xenopus Proteins
PubMed: 10943304
DOI: 10.1007/978-3-662-04264-9_4 -
The Journal of Biological Chemistry Mar 2015The GxGD proteases function to cleave protein substrates within the membrane. As these proteases contain multiple transmembrane domains typical of ion channels, we...
The GxGD proteases function to cleave protein substrates within the membrane. As these proteases contain multiple transmembrane domains typical of ion channels, we examined if GxGD proteases also function as ion channels. We tested the putative dual function by examining two archeobacterial GxGD proteases (PSH and FlaK), with known three-dimensional structures. Both are in the same GxGD family as presenilin, a protein mutated in Alzheimer Disease. Here, we demonstrate that PSH and FlaK form cation channels in lipid bilayers. A mutation that affected the enzymatic activity of FlaK rendered the channel catalytically inactive and altered the ion selectivity, indicating that the ion channel and the catalytic activities are linked. We report that the GxGD proteases, PSH and FlaK, are true "chanzymes" with interdependent ion channel and protease activity conferred by a single structural domain embedded in the membrane, supporting the proposal that higher-order proteases, including presenilin, have channel function.
Topics: Alzheimer Disease; Amyloid Precursor Protein Secretases; Animals; Archaea; Calcium Channels; Catalytic Domain; Crystallography, X-Ray; Humans; Lipid Bilayers; Membrane Proteins; Mice; Peptide Hydrolases; Presenilins; Protein Structure, Tertiary
PubMed: 25609250
DOI: 10.1074/jbc.M114.629584 -
Proceedings of the National Academy of... Nov 2017
Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Flavin-Adenine Dinucleotide; Mutation; Presenilin-1; Presenilin-2
PubMed: 29142009
DOI: 10.1073/pnas.1717180114 -
Neuro-degenerative Diseases 2008Following extracellular shedding, transmembrane domains (TMs) of beta-amyloid precursor protein (betaAPP) and Notch-1 undergo proteolysis by presenilin... (Review)
Review
BACKGROUND/AIMS
Following extracellular shedding, transmembrane domains (TMs) of beta-amyloid precursor protein (betaAPP) and Notch-1 undergo proteolysis by presenilin (PS)/gamma-secretase at least at two sites, near the middle of the TM (gamma-/S4 cleavage) and at the interface between cytosol and the TM (epsilon-/S3 cleavage), releasing Alzheimer disease (AD)-associated beta-amyloid (Abeta)/Notch-1beta (Nbeta) and betaAPP intracellular cytoplasmic domain (AICD)/Notch-1 intracellular cytoplasmic domain (NICD). Inhibiting PS/gamma-secretase activity is an essential approach to AD treatment, but it also decreases NICD production, which may cause severe side effects. Therefore, it is important to investigate the differences between the cleavages at the two sites. Gamma-/S4 and epsilon-cleavages have diversity, and produce a number of Abeta/Nbeta and AICD species. S3 cleavage diversity has been recently identified. It is significant that each cleavage occurs with strict precision, not randomly.
METHODS
Biochemical analysis of cultured cells was performed to explore the processing mechanisms.
RESULTS
Familial AD-associated PS1 mutations as well as a subset of nonsteroidal anti-inflammatory drugs cause similar changes in gamma-/S4 cleavage precision, suggesting a common process for these cleavages near the middle of the TM. While the precision of the epsilon-cleavage is drastically affected by physiological factors, that of epsilon-/S3 cleavage is not.
CONCLUSION
The processes of the two cleavages occurring in different portions of TMs may be diverse, thus representing possible targets for anti-AD therapeutics to selectively reduce Abeta.
Topics: Amyloid Precursor Protein Secretases; Amyloid beta-Peptides; Animals; Cell Membrane; Cytoplasm; Humans; Intracellular Fluid; Presenilins; Protein Processing, Post-Translational; Protein Structure, Tertiary
PubMed: 18322378
DOI: 10.1159/000113690 -
Journal of Cell Science Jul 2023One presenilin gene (PSEN) is expressed in the sea urchin embryo, in the vegetal pole of the gastrula and then mainly in cilia cells located around the digestive system...
Natural antisense transcription of presenilin in sea urchin reveals a possible role for natural antisense transcription in the general control of gene expression during development.
One presenilin gene (PSEN) is expressed in the sea urchin embryo, in the vegetal pole of the gastrula and then mainly in cilia cells located around the digestive system of the pluteus, as we recently have reported. PSEN expression must be accurately regulated for correct execution of these two steps of development. While investigating PSEN expression changes in embryos after expansion of endoderm with LiCl or of ectoderm with Zn2+ by whole-mount in situ hybridization (WISH) and quantitative PCR (qPCR), we detected natural antisense transcription of PSEN. We then found that Endo16 and Wnt5, markers of endo-mesoderm, and of Hnf6 and Gsc, markers of ectoderm, are also sense and antisense transcribed. We discuss that general gene expression could depend on both sense and antisense transcription. This mechanism, together with the PSEN gene, should be included in gene regulatory networks (GRNs) that theorize diverse processes in this species. We suggest that it would also be relevant to investigate natural antisense transcription of PSEN in the field of Alzheimer's disease (AD) where the role of human PSEN1 and PSEN2 is well known.
Topics: Humans; Animals; Presenilins; In Situ Hybridization; Gene Expression; Sea Urchins; Gene Expression Regulation, Developmental
PubMed: 37345489
DOI: 10.1242/jcs.261284 -
Journal of Diabetes Investigation Jan 2023Formation of the PEN2-ATP6AP1 complex induced by the binding of metformin to PEN2 results in the inhibition of v-ATPase activity and in the recruitment of AXIN/LKB1 to...
Formation of the PEN2-ATP6AP1 complex induced by the binding of metformin to PEN2 results in the inhibition of v-ATPase activity and in the recruitment of AXIN/LKB1 to lysosomes, which in turn results in the phosphorylation and activation of AMPK.
Topics: Humans; Metformin; Protein Serine-Threonine Kinases; AMP-Activated Protein Kinases; Lysosomes; Presenilins; Vacuolar Proton-Translocating ATPases
PubMed: 36308027
DOI: 10.1111/jdi.13925 -
Journal of Neurochemistry Mar 2016Presenilins have been reported to regulate calcium homeostasis in the endoplasmic reticulum, and dysregulation of intracellular calcium has been implicated in the...
Presenilins have been reported to regulate calcium homeostasis in the endoplasmic reticulum, and dysregulation of intracellular calcium has been implicated in the pathogenesis of Alzheimer's disease (AD). Reduced endoproteolysis levels of presenilin-1 (PS1) have been detected in postmortem brains of patients carrying familial Alzheimer's disease PS1 mutations. This study deals with the effect of attenuated endoproteolysis of PS1 on store-operated calcium (SOC) entry in neuronal cells and mouse fibroblasts with double knockouts of PS1 and PS2. Significant enhancement of SOC channel activation has been detected by electrophysiological measurements in cells with reduced PS1 endoproteolysis. The increase in SOC entry was not accompanied by any changes in protein levels of channels subunits or stromal interaction molecule. These data are important for understanding the role of PS1 in AD, apart from its involvement in γ-secretase cleavage of amyloid precursor protein into Aβ. Taking into account that most of familial AD-connected mutations in PS1 are loss-of-function, the observed effects may well be general for familial AD. Reduced endoproteolysis levels of presenilin-1 (PS1) have been detected in postmortem brains of patients carrying familial Alzheimer's disease PS1 mutations. Significant enhancement of SOC channel activation has been detected by electrophysiological measurements in cells with reduced PS1 endoproteolysis. The data obtained shed light on Alzheimer's disease pathogenesis and implicates to the future drugs development.
Topics: Alzheimer Disease; Amyloid Precursor Protein Secretases; Amyloid beta-Protein Precursor; Animals; Calcium; Endoplasmic Reticulum; Humans; Mice; Mutation; Neurons; Presenilin-1; Presenilin-2
PubMed: 26678016
DOI: 10.1111/jnc.13495 -
The Journal of Neuroscience : the... Feb 2011Presenilins are ubiquitous, intramembrane proteins that function in Alzheimer's disease (AD) as the catalytic component of the γ-secretase complex. Familial AD...
Presenilins are ubiquitous, intramembrane proteins that function in Alzheimer's disease (AD) as the catalytic component of the γ-secretase complex. Familial AD mutations in presenilin are known to exacerbate lysosomal pathology. Hence, we sought to elucidate the function endogenous, wild-type presenilins play in autophagy-mediated protein degradation. We report the finding that genetic deletion or knockdown of presenilins alters many autophagy-related proteins demonstrating a buildup of autophagosomes, indicative of dysfunction in the system. Presenilin-deficient cells inefficiently clear long-lived proteins and fail to build up autophagosomes when challenged with lysosomal inhibitors. Our studies further show that γ-secretase inhibitors do not adversely impact autophagy, indicating that the role of presenilins in autophagy is independent of γ-secretase activity. Based on our findings, we conclude that endogenous, wild-type presenilins are necessary for proper protein degradation through the autophagosome-lysosome system by functioning at the lysosomal level. The role of presenilins in autophagy has many implications for its function in neurological diseases such as AD.
Topics: Alzheimer Disease; Amyloid Precursor Protein Secretases; Animals; Autophagy; Cell Line, Tumor; Cells, Cultured; Lysosomes; Mice; Neurons; Presenilin-1; Presenilin-2; Proteins
PubMed: 21414900
DOI: 10.1523/JNEUROSCI.5156-10.2010