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Michael S Wolfe - One of the best experts on this subject based on the ideXlab platform.
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Dysfunctional γ-Secretase in Familial Alzheimer’s Disease
Neurochemical Research, 2019Co-Authors: Michael S WolfeAbstract:Genetics strongly implicate the amyloid β-peptide (Aβ) in the pathogenesis of Alzheimer’s disease. Dominant missense mutation in the Presenilins and the amyloid precursor protein (APP) cause early-onset familial Alzheimer’s disease (FAD). As Presenilin is the catalytic component of the γ-secretase protease complex that produces Aβ from APP, mutation of the enzyme or substrate that produce Aβ leads to FAD. However, the mechanism by which Presenilin mutations cause FAD has been controversial, with gain of function and loss of function offered as binary choices. This overview will instead present the case that Presenilins are dysfunctional in FAD. γ-Secretase is a multi-functional enzyme that proteolyzes the APP transmembrane domain in a complex and processive manner. Reduction in a specific function—the carboxypeptidase trimming of initially formed long Aβ peptides containing most of the transmembrane domain to shorter secreted forms—is an emerging common feature of FAD-mutant γ-secretase complexes.
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Dysfunctional γ-Secretase in Familial Alzheimer's Disease.
Neurochemical Research, 2018Co-Authors: Michael S WolfeAbstract:Genetics strongly implicate the amyloid β-peptide (Aβ) in the pathogenesis of Alzheimer’s disease. Dominant missense mutation in the Presenilins and the amyloid precursor protein (APP) cause early-onset familial Alzheimer’s disease (FAD). As Presenilin is the catalytic component of the γ-secretase protease complex that produces Aβ from APP, mutation of the enzyme or substrate that produce Aβ leads to FAD. However, the mechanism by which Presenilin mutations cause FAD has been controversial, with gain of function and loss of function offered as binary choices. This overview will instead present the case that Presenilins are dysfunctional in FAD. γ-Secretase is a multi-functional enzyme that proteolyzes the APP transmembrane domain in a complex and processive manner. Reduction in a specific function—the carboxypeptidase trimming of initially formed long Aβ peptides containing most of the transmembrane domain to shorter secreted forms—is an emerging common feature of FAD-mutant γ-secretase complexes.
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Toward the structure of Presenilin/γ-secretase and Presenilin homologs.
Biochimica et biophysica acta, 2013Co-Authors: Michael S WolfeAbstract:Presenilin is the catalytic component of the γ-secretase complex, a membrane-embedded aspartyl protease that plays a central role in biology and in the pathogenesis of Alzheimer's disease. Upon assembly with its three protein cofactors (nicastrin, Aph-1 and Pen-2), Presenilin undergoes autoproteolysis into two subunits, each of which contributes one of the catalytic aspartates to the active site. A family of Presenilin homologs, including signal peptide peptidase, possess proteolytic activity without the need for other protein factors, and these simpler intramembrane aspartyl proteases have given insight into the action of Presenilin within the γ-secretase complex. Cellular and molecular studies support a nine-transmembrane topology for Presenilins and their homologs, and small-molecule inhibitors and cysteine scanning with crosslinking have suggested certain Presenilin residues and regions that contribute to substrate recognition and handling. Identification of partial complexes has also offered clues to protein-protein interactions within the γ-secretase complex. Biophysical methods have allowed 3D views of the γ-secretase complex and Presenilins. Most recently, the crystal structure of a microbial Presenilin homolog has confirmed a nine-transmembrane topology and intramembranous location and proximity of the two conserved and essential aspartates. The crystal structure also provides a platform for the formulation of specific hypotheses regarding substrate interaction and catalysis as well as the pathogenic mechanism of Alzheimer-causing Presenilin mutations. This article is part of a Special Issue entitled: Intramembrane Proteases.
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γ-Secretase inhibitors as molecular probes of Presenilin function
Journal of molecular neuroscience : MN, 2001Co-Authors: Michael S WolfeAbstract:Mutations in the Presenilins cause Alzheimer’s disease (AD) and alter γ-secretase activity to increase the production of the 42-residue amyloid-β peptide (Aβ) found disproportionally in the cerebral plaques that characterize the disease. The serpentine Presenilins are required for transmembrane cleavage of both the amyloid-β precursor protein (APP) and the Notch receptor by γ-secretase, and Presenilins are biochemically associated with the protease. Inhibitors of γ-secretase have provided critical clues to the function of Presenilins. Pharmacological profiling suggested that γ-secretase is an aspartyl protease, leading to the identification of two conserved aspartates important to Presenilin’s role in proteolysis. Conversion of transition-state analogue inhibitors of γ-secretase to affinity reagents resulted in specific tagging of the heterodimeric form of Presenilins, strongly suggesting that the active site of γ-secretase lies at the interface of the Presenilin heterodimer. Heterodimeric Presenilin appears to be the catalytic portion of a multi-protein γ-secretase complex.
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the transmembrane aspartates in Presenilin 1 and 2 are obligatory for γ secretase activity and amyloid β protein generation
Journal of Biological Chemistry, 2000Co-Authors: Taylor W Kimberly, Michael S Wolfe, Talat Rahmati, Dennis J. SelkoeAbstract:Abstract The discovery that a deficiency of Presenilin 1 (PS1) decreases the production of amyloid β-protein (Aβ) identified the Presenilins as important mediators of the γ-secretase cleavage of β-amyloid precursor protein (APP). Recently, we found that two conserved transmembrane (TM) aspartates in PS1 are critical for Aβ production, providing evidence that PS1 either functions as a required diaspartyl cofactor for γ-secretase or is itself γ-secretase. Presenilin 2 (PS2) shares substantial sequence and possibly functional homology with PS1. Here, we show that the two TM aspartates in PS2 are also critical for γ-secretase activity, providing further evidence that PS2 is functionally homologous to PS1. Cells stably co-expressing TM Asp → Ala mutations in both PS1 and PS2 show further accumulation of the APP-derived γ-secretase substrates, C83 and C99. The production of Aβ is reduced to undetectable levels in the conditioned media of these cells. Furthermore, endoproteolysis of the exogenous Asp mutant PS2 is absent, and endogenous PS1 C-terminal fragments are diminished to undetectable levels. Therefore, the co-expression of PS1 and PS2 TM Asp → Ala mutants suppresses the formation of any detectable PS1 or PS2 heterodimeric fragments and essentially abolishes the production of Aβ. These results explain the residual Aβ production seen in PS1-deficient cells and demonstrate the absolute requirement of functional Presenilins for Aβ generation. We conclude that Presenilins, and their TM aspartates in particular, are attractive targets for lowering Aβ therapeutically to prevent Alzheimer's disease.
Iva Greenwald - One of the best experts on this subject based on the ideXlab platform.
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Presenilin is required for activity and nuclear access of notch in drosophila
Nature, 1999Co-Authors: Gary Struhl, Iva GreenwaldAbstract: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.
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additional evidence for an eight transmembrane domain topology for caenorhabditis elegans and human Presenilins
Proceedings of the National Academy of Sciences of the United States of America, 1998Co-Authors: Xiajun Li, Iva GreenwaldAbstract:Presenilins have been implicated in the genesis of Alzheimer’s disease and in facilitating LIN-12/Notch activity during development. All Presenilins have multiple hydrophobic regions that could theoretically span a membrane, and a description of the membrane topology is a crucial step toward deducing the mechanism of Presenilin function. Previously, we proposed an eight-transmembrane-domain model for Presenilin, based on studies of the Caenorhabditis elegans SEL-12 Presenilin. Here, we describe experiments that support the view that two of the hydrophobic regions of SEL-12 function as the seventh and eighth transmembrane domains. Furthermore, we have shown that human Presenilin 1 behaves like SEL-12 Presenilin when analyzed by our methods. Our results provide additional experimental support for the eight-transmembrane-domain model of Presenilin topology.
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HOP-1, A CAENORHABDITIS ELEGANS Presenilin, APPEARS TO BE FUNCTIONALLY REDUNDANT WITH SEL-12 Presenilin AND TO FACILITATE LIN-12 AND GLP-1 SIGNALING
Proceedings of the National Academy of Sciences of the United States of America, 1997Co-Authors: Iva GreenwaldAbstract:Mutant Presenilins have been found to cause Alzheimer disease. Here, we describe the identification and characterization of HOP-1, a Caenorhabditis elegans Presenilin that displays much more lower sequence identity with human Presenilins than does the other C. elegans Presenilin, SEL-12. Despite considerable divergence, HOP-1 appears to be a bona fide Presenilin, because HOP-1 can rescue the egg-laying defect caused by mutations in sel-12 when hop-1 is expressed under the control of sel-12 regulatory sequences. HOP-1 also has the essential topological characteristics of the other Presenilins. Reducing hop-1 activity in a sel-12 mutant background causes synthetic lethality and terminal phenotypes associated with reducing the function of the C. elegans lin-12 and glp-1 genes. These observations suggest that hop-1 is functionally redundant with sel-12 and underscore the intimate connection between Presenilin activity and LIN-12/Notch activity inferred from genetic studies in C. elegans and mammals.
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ASSESSMENT OF NORMAL AND MUTANT HUMAN Presenilin FUNCTION IN CAENORHABDITIS ELEGANS
Proceedings of the National Academy of Sciences of the United States of America, 1996Co-Authors: Diane Levitan, Timothy G. Doyle, Denise Brousseau, Michael K. Lee, Gopal Thinakaran, Hilda H. Slunt, Sangram S. Sisodia, Iva GreenwaldAbstract:We provide evidence that normal human Presenilins can substitute for Caenorhabditis elegans SEL-12 protein in functional assays in vivo . In addition, six familial Alzheimer disease-linked mutant human Presenilins were tested and found to have reduced ability to rescue the sel-12 mutant phenotype, suggesting that they have lower than normal Presenilin activity. A human Presenilin 1 deletion variant that fails to be proteolytically processed and a mutant SEL-12 protein that lacks the C terminus display considerable activity in this assay, suggesting that neither Presenilin proteolysis nor the C terminus is absolutely required for normal Presenilin function. We also show that sel-12 is expressed in most neural and nonneural cell types in all developmental stages. The reduced activity of mutant Presenilins and as yet unknown gain-of-function properties may be a contributing factor in the development of Alzheimer disease.
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Membrane Topology of the C. elegans SEL-12 Presenilin
Neuron, 1996Co-Authors: Iva GreenwaldAbstract:Abstract Mutant Presenilins cause Alzheimer's disease. Presenilins have multiple hydrophobic regions that could theoretically span a membrane, and a knowledge of the membrane topology is crucial for deducing the mechanism of Presenilin function. By analyzing the activity of β-galactosidase hybrid proteins expressed in C. elegans, we show that the C. elegans SEL-12 Presenilin has eight transmembrane domains and that there is a cleavage site after the sixth transmembrane domain. We examine the Presenilin sequence in view of the predicted topology and discuss possible mechanisms for Presenilin function.
Toshitaka Kawarai - One of the best experts on this subject based on the ideXlab platform.
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The gamma/epsilon-secretase-derived APP intracellular domain fragments regulate p53.
Current Alzheimer Research, 2007Co-Authors: Frédéric Checler, Toshitaka Kawarai, Peter St George-hyslop, Jean Sevalle, Raphaëlle Pardossi-piquard, Claire Sunyach, Bruno Vincent, Nadège Girardot, Cristine Alves Da CostaAbstract:Amyloid beta-peptide (Abeta), which plays a central role in Alzheimer Disease, is generated by Presenilin-dependent and Presenilin-independent gamma-secretase cleavages of beta-amyloid precursor protein (betaAPP). We report that the Presenilins (PS1 and PS2) also regulate p53-associated cell death. Thus, we established that PS deficiency, catalytically inactive PS mutants, gamma-secretase inhibitors and betaAPP or APLP2 depletion reduced the expression and activity of p53, and lowered the transactivation of its promoter and mRNA levels. p53 expression was also reduced in the brains or betaAPP-deficient mice or in brains where both PS had been invalidated by double conditional knock out. AICDC59 and AICDC50, the gamma- and epsilon-secretase-derived C-terminal fragments of betaAPP, respectively, trigger the activation of caspase-3, p53-dependent cell death, and increase p53 activity and mRNA. Finally, HEK293 cells expressing PS1 harboring familial AD (FAD) mutations or FAD-affected brains, all display enhanced p53 activity and p53 expression. Our studies demonstrate that AICDs control p53 at a transcriptional level, in vitro and in vivo and unravel a still unknown function for Presenilins.
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aph 1 interacts with mature and immature forms of Presenilins and nicastrin and may play a role in maturation of Presenilin nicastrin complexes
Journal of Biological Chemistry, 2003Co-Authors: Fusheng Chen, Anurag Tandon, Toshitaka Kawarai, Nobuo Sanjo, Hiroshi Hasegawa, Xueying Ruan, Monica Duthie, Anchla Luthra, Howard T J Mount, Paul E. FraserAbstract:APH-1 and PEN-2 genes modulate the function of nicastrin and the Presenilins in Caenorhabditis elegans. Preliminary studies in transfected mammalian cells overexpressing tagged APH-1 proteins suggest that this genetic interaction is mediated by a direct physical interaction. Using the APH-1 protein encoded on human chromosome 1 (APH-1(1)L; also known as APH-1a) as an archetype, we report here that endogenous forms of APH-1 are predominantly expressed in intracellular membrane compartments, including the endoplasmic reticulum and cis-Golgi. APH-1 proteins directly interact with immature and mature forms of the Presenilins and nicastrin within high molecular weight complexes that display gamma- and epsilon-secretase activity. Indeed APH-1 proteins can bind to the nicastrin delta312-369 loss of function mutant, which does not undergo glycosylation maturation and is not trafficking beyond the endoplasmic reticulum. The levels of expression of endogenous APH-1(1)L can be suppressed by overexpression of any other members of the APH-1 family, suggesting that their abundance is coordinately regulated. Finally, although the absence of APH-1 destabilizes the Presenilins, in contrast to nicastrin and PEN-2, APH-1 itself is only modestly destabilized in cells lacking functional expression of Presenilin 1 or Presenilin 2. Taken together, our data suggest that APH-1 proteins, and APH-1(1) in particular, may have a role in the initial assembly and maturation of Presenilin.nicastrin complexes.
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mutation of conserved aspartates affect maturation of Presenilin 1 and Presenilin 2 complexes
Acta Neurologica Scandinavica, 2000Co-Authors: Gang Yu, Anurag Tandon, Masaki Nishimura, Toshitaka Kawarai, Harald Steiner, Fusheng ChenAbstract:Presenilin (PS1 and PS2) holoproteins are transiently incorporated into low molecular weight (MW) complexes. During subsequent incorporation into a higher MW complex, they undergo endoproteolysis to generate stable N- and C-terminal fragments (NTF/CTF). Mutation of either of two conserved aspartate residues in transmembrane domains inhibits both Presenilin-endoproteolysis and the proteolytic processing of APP and Notch. We show that aspartate-mutant holoprotein Presenilins are not incorporated into the high molecular weight, NTF/CTF-containing complexes. Aspartate-mutant Presenilin holoproteins also preclude entry of endogenous wild-type PS1/PS2 into the high molecular weight complexes, but do not affect the incorporation of wild-type holoproteins into lower molecular weight holoprotein complexes. These data suggest that the loss-of-function aspartate-mutants cause altered PS complex maturation, and argue that the functional Presenilin moieties are contained in the high molecular weight Presenilin NTF/CTF-containing complexes.
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nicastrin modulates Presenilin mediated notch glp 1 signal transduction and βapp processing
Nature, 2000Co-Authors: Masaki Nishimura, Anurag Tandon, Toshitaka Kawarai, Fusheng Chen, Diane Levitan, Shigeki Arawaka, Ekaterina Rogaeva, Lili Zhang, Youqiang Song, Agnes SupalaAbstract:Nicastrin, a transmembrane glycoprotein, forms high molecular weight complexes with Presenilin 1 and Presenilin 2. Suppression of nicastrin expression in Caenorhabditis elegans embryos induces a subset of notch/glp-1 phenotypes similar to those induced by simultaneous null mutations in both Presenilin homologues of C. elegans (sel-12 and hop-1). Nicastrin also binds carboxy-terminal derivatives of β-amyloid precursor protein (βAPP), and modulates the production of the amyloid β-peptide (Aβ) from these derivatives. Missense mutations in a conserved hydrophilic domain of nicastrin increase Aβ42 and Aβ40 peptide secretion. Deletions in this domain inhibit Aβ production. Nicastrin and Presenilins are therefore likely to be functional components of a multimeric complex necessary for the intramembranous proteolysis of proteins such as Notch/GLP-1 and βAPP.
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mutation of conserved aspartates affects maturation of both aspartate mutant and endogenous Presenilin 1 and Presenilin 2 complexes
Journal of Biological Chemistry, 2000Co-Authors: Gang Yu, Anurag Tandon, Masaki Nishimura, Toshitaka Kawarai, Harald Steiner, Fusheng ChenAbstract:Abstract Presenilin (PS1 and PS2) holoproteins are transiently incorporated into low molecular weight (MW) complexes. During subsequent incorporation into a higher MW complex, they undergo endoproteolysis to generate stable N- and C-terminal fragments. Mutation of either of two conserved aspartate residues in transmembrane domains inhibits both Presenilin-endoproteolysis and the proteolytic processing of β-amyloid precursor protein and Notch. We show that although PS1/PS2 endoproteolysis is not required for inclusion into the higher MW N- and C-terminal fragment-containing complex, aspartate mutant holoprotein Presenilins are not incorporated into the high MW complexes. Aspartate mutant Presenilin holoproteins also preclude entry of endogenous wild type PS1/PS2 into the high MW complexes but do not affect the incorporation of wild type holoproteins into lower MW holoprotein complexes. These data suggest that the loss of function effects of the aspartate mutants result in altered PS complex maturation and argue that the functional Presenilin moieties are contained in the high molecular weight complexes.
Anurag Tandon - One of the best experts on this subject based on the ideXlab platform.
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Presenilin 1 and Presenilin 2 have differential effects on the stability and maturation of nicastrin in Mammalian brain.
The Journal of biological chemistry, 2003Co-Authors: Fusheng Chen, Anurag Tandon, Shigeki Arawaka, Nobuo Sanjo, Hiroshi Hasegawa, Frank S. Lee, Xueying Ruan, Peter Mastrangelo, Serap ErdebilAbstract:The Presenilins and nicastrin form high molecular mass, multimeric protein complexes involved in the intramembranous proteolysis of several proteins. Post-translational glycosylation and trafficking of nicastrin is necessary for the activity of these complexes. We report here that although there are differences in the post-translational processing of nicastrin in neurons and glia, both of the Presenilins are required for the physiological post-translational modification and for the correct subcellular distribution of nicastrin. Absence of Presenilin 1 (PS1) is associated with dramatic reductions in the level of mature glycosylated nicastrin and with redistribution of nicastrin away from the cell surface. In contrast, absence of Presenilin 2 (PS2) is associated with only modest reductions in the levels of immature nicastrin. It is notable that these differential effects parallel the differential effects of null mutations in PS1 and PS2 on APP and Notch processing. Our data therefore suggest that the differential interactions of PS1 and PS2 with nicastrin reflect different functions for the PS1 and PS2 complexes.
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aph 1 interacts with mature and immature forms of Presenilins and nicastrin and may play a role in maturation of Presenilin nicastrin complexes
Journal of Biological Chemistry, 2003Co-Authors: Fusheng Chen, Anurag Tandon, Toshitaka Kawarai, Nobuo Sanjo, Hiroshi Hasegawa, Xueying Ruan, Monica Duthie, Anchla Luthra, Howard T J Mount, Paul E. FraserAbstract:APH-1 and PEN-2 genes modulate the function of nicastrin and the Presenilins in Caenorhabditis elegans. Preliminary studies in transfected mammalian cells overexpressing tagged APH-1 proteins suggest that this genetic interaction is mediated by a direct physical interaction. Using the APH-1 protein encoded on human chromosome 1 (APH-1(1)L; also known as APH-1a) as an archetype, we report here that endogenous forms of APH-1 are predominantly expressed in intracellular membrane compartments, including the endoplasmic reticulum and cis-Golgi. APH-1 proteins directly interact with immature and mature forms of the Presenilins and nicastrin within high molecular weight complexes that display gamma- and epsilon-secretase activity. Indeed APH-1 proteins can bind to the nicastrin delta312-369 loss of function mutant, which does not undergo glycosylation maturation and is not trafficking beyond the endoplasmic reticulum. The levels of expression of endogenous APH-1(1)L can be suppressed by overexpression of any other members of the APH-1 family, suggesting that their abundance is coordinately regulated. Finally, although the absence of APH-1 destabilizes the Presenilins, in contrast to nicastrin and PEN-2, APH-1 itself is only modestly destabilized in cells lacking functional expression of Presenilin 1 or Presenilin 2. Taken together, our data suggest that APH-1 proteins, and APH-1(1) in particular, may have a role in the initial assembly and maturation of Presenilin.nicastrin complexes.
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The Presenilins
Genome Biology, 2002Co-Authors: Anurag Tandon, Paul FraserAbstract:The Presenilins are evolutionarily conserved transmembrane proteins that regulate cleavage of certain other proteins in their transmembrane domains. The clinical significance of this regulation is shown by the contribution of Presenilin mutations to 20-50% of early-onset cases of inherited Alzheimer's disease. Although the precise molecular mechanism underlying Presenilin function or dysfunction remains elusive, Presenilins are thought to be part of a complex of proteins that has 'γ-secretase cleavage' activity, which is clearly central in the pathogenesis of Alzheimer's disease. Mutations in Presenilins increase the production of the longer isoforms of amyloid β peptide, which are neurotoxic and prone to self-aggregation. Biochemical studies indicate that the Presenilins do not act alone but operate within large heteromeric protein complexes, whose components and enzymatic core are the subject of much study and controversy; one essential component is nicastrin. The Presenilin primary sequence is remarkably well conserved in eukaryotes, suggesting some functional conservation; indeed, defects caused by mutations in the nemotode Presenilin homolog can be rescued by human Presenilin.
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The Presenilins.
Genome biology, 2002Co-Authors: Anurag Tandon, Paul FraserAbstract:The Presenilins are evolutionarily conserved transmembrane proteins that regulate cleavage of certain other proteins in their transmembrane domains. The clinical significance of this regulation is shown by the contribution of Presenilin mutations to 20-50% of early-onset cases of inherited Alzheimer's disease. Although the precise molecular mechanism underlying Presenilin function or dysfunction remains elusive, Presenilins are thought to be part of a complex of proteins that has 'gamma-secretase cleavage' activity, which is clearly central in the pathogenesis of Alzheimer's disease. Mutations in Presenilins increase the production of the longer isoforms of amyloid beta peptide, which are neurotoxic and prone to self-aggregation. Biochemical studies indicate that the Presenilins do not act alone but operate within large heteromeric protein complexes, whose components and enzymatic core are the subject of much study and controversy; one essential component is nicastrin. The Presenilin primary sequence is remarkably well conserved in eukaryotes, suggesting some functional conservation; indeed, defects caused by mutations in the nemotode Presenilin homolog can be rescued by human Presenilin.
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mutation of conserved aspartates affect maturation of Presenilin 1 and Presenilin 2 complexes
Acta Neurologica Scandinavica, 2000Co-Authors: Gang Yu, Anurag Tandon, Masaki Nishimura, Toshitaka Kawarai, Harald Steiner, Fusheng ChenAbstract:Presenilin (PS1 and PS2) holoproteins are transiently incorporated into low molecular weight (MW) complexes. During subsequent incorporation into a higher MW complex, they undergo endoproteolysis to generate stable N- and C-terminal fragments (NTF/CTF). Mutation of either of two conserved aspartate residues in transmembrane domains inhibits both Presenilin-endoproteolysis and the proteolytic processing of APP and Notch. We show that aspartate-mutant holoprotein Presenilins are not incorporated into the high molecular weight, NTF/CTF-containing complexes. Aspartate-mutant Presenilin holoproteins also preclude entry of endogenous wild-type PS1/PS2 into the high molecular weight complexes, but do not affect the incorporation of wild-type holoproteins into lower molecular weight holoprotein complexes. These data suggest that the loss-of-function aspartate-mutants cause altered PS complex maturation, and argue that the functional Presenilin moieties are contained in the high molecular weight Presenilin NTF/CTF-containing complexes.
Masaki Nishimura - One of the best experts on this subject based on the ideXlab platform.
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mutation of conserved aspartates affect maturation of Presenilin 1 and Presenilin 2 complexes
Acta Neurologica Scandinavica, 2000Co-Authors: Gang Yu, Anurag Tandon, Masaki Nishimura, Toshitaka Kawarai, Harald Steiner, Fusheng ChenAbstract:Presenilin (PS1 and PS2) holoproteins are transiently incorporated into low molecular weight (MW) complexes. During subsequent incorporation into a higher MW complex, they undergo endoproteolysis to generate stable N- and C-terminal fragments (NTF/CTF). Mutation of either of two conserved aspartate residues in transmembrane domains inhibits both Presenilin-endoproteolysis and the proteolytic processing of APP and Notch. We show that aspartate-mutant holoprotein Presenilins are not incorporated into the high molecular weight, NTF/CTF-containing complexes. Aspartate-mutant Presenilin holoproteins also preclude entry of endogenous wild-type PS1/PS2 into the high molecular weight complexes, but do not affect the incorporation of wild-type holoproteins into lower molecular weight holoprotein complexes. These data suggest that the loss-of-function aspartate-mutants cause altered PS complex maturation, and argue that the functional Presenilin moieties are contained in the high molecular weight Presenilin NTF/CTF-containing complexes.
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nicastrin modulates Presenilin mediated notch glp 1 signal transduction and βapp processing
Nature, 2000Co-Authors: Masaki Nishimura, Anurag Tandon, Toshitaka Kawarai, Fusheng Chen, Diane Levitan, Shigeki Arawaka, Ekaterina Rogaeva, Lili Zhang, Youqiang Song, Agnes SupalaAbstract:Nicastrin, a transmembrane glycoprotein, forms high molecular weight complexes with Presenilin 1 and Presenilin 2. Suppression of nicastrin expression in Caenorhabditis elegans embryos induces a subset of notch/glp-1 phenotypes similar to those induced by simultaneous null mutations in both Presenilin homologues of C. elegans (sel-12 and hop-1). Nicastrin also binds carboxy-terminal derivatives of β-amyloid precursor protein (βAPP), and modulates the production of the amyloid β-peptide (Aβ) from these derivatives. Missense mutations in a conserved hydrophilic domain of nicastrin increase Aβ42 and Aβ40 peptide secretion. Deletions in this domain inhibit Aβ production. Nicastrin and Presenilins are therefore likely to be functional components of a multimeric complex necessary for the intramembranous proteolysis of proteins such as Notch/GLP-1 and βAPP.
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mutation of conserved aspartates affects maturation of both aspartate mutant and endogenous Presenilin 1 and Presenilin 2 complexes
Journal of Biological Chemistry, 2000Co-Authors: Gang Yu, Anurag Tandon, Masaki Nishimura, Toshitaka Kawarai, Harald Steiner, Fusheng ChenAbstract:Abstract Presenilin (PS1 and PS2) holoproteins are transiently incorporated into low molecular weight (MW) complexes. During subsequent incorporation into a higher MW complex, they undergo endoproteolysis to generate stable N- and C-terminal fragments. Mutation of either of two conserved aspartate residues in transmembrane domains inhibits both Presenilin-endoproteolysis and the proteolytic processing of β-amyloid precursor protein and Notch. We show that although PS1/PS2 endoproteolysis is not required for inclusion into the higher MW N- and C-terminal fragment-containing complex, aspartate mutant holoprotein Presenilins are not incorporated into the high MW complexes. Aspartate mutant Presenilin holoproteins also preclude entry of endogenous wild type PS1/PS2 into the high MW complexes but do not affect the incorporation of wild type holoproteins into lower MW holoprotein complexes. These data suggest that the loss of function effects of the aspartate mutants result in altered PS complex maturation and argue that the functional Presenilin moieties are contained in the high molecular weight complexes.
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Presenilin structure, function and role in Alzheimer disease.
Biochimica et biophysica acta, 2000Co-Authors: Paul E. Fraser, Masaki Nishimura, Dun-sheng Yang, Lyne Levesque, Shigeki Arawaka, Louise C. Serpell, Ekaterina Rogaeva, Peter St George-hyslopAbstract:Numerous missense mutations in the Presenilins are associated with the autosomal dominant form of familial Alzheimer disease. Presenilin genes encode polytopic transmembrane proteins, which are processed by proteolytic cleavage and form high-molecular-weight complexes under physiological conditions. The Presenilins have been suggested to be functionally involved in developmental morphogenesis, unfolded protein responses and processing of selected proteins including the s-amyloid precursor protein. Although the underlying mechanism by which Presenilin mutations lead to development of Alzheimer disease remains elusive, one consistent mutational effect is an overproduction of long-tailed amyloid s-peptides. Furthermore, Presenilins interact with s-catenin to form Presenilin complexes, and the physiological and mutational effects are also observed in the catenin signal transduction pathway.
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Biology of Presenilins as causative molecules for Alzheimer disease
Clinical genetics, 1999Co-Authors: Masaki Nishimura, Peter St George-hyslopAbstract:Many missense mutations in the Presenilins are associated with autosomal dominant forms of familial Alzheimer disease (AD). Presenilin genes encode polytopic transmembrane proteins, which are processed by proteolytic cleavage and form high-molecular-weight complexes under physiological conditions. The Presenilins have been suggested to be functionally involved in developmental morphogenesis, apoptosis signal pathways, and processing of selected proteins including beta-amyloid precursor protein. Although the underlying mechanism in which Presenilin mutations lead to development of AD remains elusive, one consistent mutational effect is an overproduction of long-tailed amyloid beta-peptides. Furthermore, Presenilins interact with beta-catenin to form Presenilin complexes and Presenilin mutations effect beta-catenin signalling pathways.
