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Presenilin

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https://www.readbyqxmd.com/read/28350801/app-psen1-and-psen2-mutations-in-early-onset-alzheimer-disease-a-genetic-screening-study-of-familial-and-sporadic-cases
#1
Hélène-Marie Lanoiselée, Gaël Nicolas, David Wallon, Anne Rovelet-Lecrux, Morgane Lacour, Stéphane Rousseau, Anne-Claire Richard, Florence Pasquier, Adeline Rollin-Sillaire, Olivier Martinaud, Muriel Quillard-Muraine, Vincent de la Sayette, Claire Boutoleau-Bretonniere, Frédérique Etcharry-Bouyx, Valérie Chauviré, Marie Sarazin, Isabelle le Ber, Stéphane Epelbaum, Thérèse Jonveaux, Olivier Rouaud, Mathieu Ceccaldi, Olivier Félician, Olivier Godefroy, Maite Formaglio, Bernard Croisile, Sophie Auriacombe, Ludivine Chamard, Jean-Louis Vincent, Mathilde Sauvée, Cecilia Marelli-Tosi, Audrey Gabelle, Canan Ozsancak, Jérémie Pariente, Claire Paquet, Didier Hannequin, Dominique Campion
BACKGROUND: Amyloid protein precursor (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2) mutations cause autosomal dominant forms of early-onset Alzheimer disease (AD-EOAD). Although these genes were identified in the 1990s, variant classification remains a challenge, highlighting the need to colligate mutations from large series. METHODS AND FINDINGS: We report here a novel update (2012-2016) of the genetic screening of the large AD-EOAD series ascertained across 28 French hospitals from 1993 onwards, bringing the total number of families with identified mutations to n = 170...
March 2017: PLoS Medicine
https://www.readbyqxmd.com/read/28332150/dynamic-nature-of-presenilin1-%C3%AE-secretase-implication-for-alzheimer-s-disease-pathogenesis
#2
REVIEW
Katarzyna Marta Zoltowska, Oksana Berezovska
Presenilin 1 (PS1) is a catalytic component of the γ-secretase complex, responsible for the intramembraneous cleavage of more than 90 type I transmembrane proteins, including Alzheimer's disease (AD)-related amyloid precursor protein (APP). The γ-secretase-mediated cleavage of the APP C-terminal membrane stub leads to the production of various amyloid β (Aβ) species. The assembly of Aβ into neurotoxic oligomers, which causes synaptic dysfunction and neurodegeneration, is influenced by the relative ratio of the longer (Aβ42/43) to shorter Aβ (Aβ40) peptides...
March 22, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28326725/-analysis-of-salivary-protease-spectrum-in-chronic-periodontitis
#3
Li Qian, Zhou Xuedong, Fan Yaping, Yang Tengyu, Wu Songtao, Yu Yu, Chen Jiao, Zhang Ping, Feng Yun
OBJECTIVE: This study aimed to investigate the difference in salivary protease expression in patients with chronic periodontitis and normal individuals. METHODS: The stimulating saliva in patients with chronic periodontitis and normal individuals were collected. Protein chip technology was adapted to analyze salivary protease spectrum. RESULTS: Among the 34 proteases in the chip, disintegrin and metalloproteinase (ADAM)8, matrix metalloproteinase (MMP)-8, MMP-12, neprilysin/CD10, and uridylyl phosphate adenosine/urokinase showed a significantly increased concentration in the saliva of chronic periodontitis patients compared with those in the saliva of normal individuals (P<0...
February 1, 2017: Hua Xi Kou Qiang Yi Xue za Zhi, Huaxi Kouqiang Yixue Zazhi, West China Journal of Stomatology
https://www.readbyqxmd.com/read/28320827/structural-and-chemical-biology-of-presenilin-complexes
#4
Douglas S Johnson, Yue-Ming Li, Martin Pettersson, Peter H St George-Hyslop
The presenilin proteins are the catalytic subunits of a tetrameric complex containing presenilin 1 or 2, anterior pharynx defective 1 (APH1), nicastrin, and PEN-2. Other components such as TMP21 may exist in a subset of specialized complexes. The presenilin complex is the founding member of a unique class of aspartyl proteases that catalyze the γ, ɛ, ζ site cleavage of the transmembrane domains of Type I membrane proteins including amyloid precursor protein (APP) and Notch. Here, we detail the structural and chemical biology of this unusual enzyme...
March 20, 2017: Cold Spring Harbor Perspectives in Medicine
https://www.readbyqxmd.com/read/28302486/mitochondria-are-devoid-of-amyloid-%C3%AE-protein-a%C3%AE-producing-secretases-evidence-for-unlikely-occurrence-within-mitochondria-of-a%C3%AE-generation-from-amyloid-precursor-protein
#5
Naomi Mamada, Daisuke Tanokashira, Kazuhiro Ishii, Akira Tamaoka, Wataru Araki
Mitochondrial dysfunction is implicated in the pathological mechanism of Alzheimer's disease (AD). Amyloid β-protein (Aβ), which plays a central role in AD pathogenesis, is reported to accumulate within mitochondria. However, a question remains as to whether Aβ is generated locally from amyloid precursor protein (APP) within mitochondria. We investigated this issue by analyzing the expression patterns of APP, APP-processing secretases, and APP metabolites in mitochondria separated from human neuroblastoma SH-SY5Y cells and those expressing Swedish mutant APP...
March 13, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28287404/mutations-in-%C3%AE-secretase-subunit-encoding-psenen-underlie-dowling-degos-disease-associated-with-acne-inversa
#6
Damian J Ralser, F Buket Ü Basmanav, Aylar Tafazzoli, Jade Wititsuwannakul, Sarah Delker, Sumita Danda, Holger Thiele, Sabrina Wolf, Michélle Busch, Susanne A Pulimood, Janine Altmüller, Peter Nürnberg, Didier Lacombe, Uwe Hillen, Jörg Wenzel, Jorge Frank, Benjamin Odermatt, Regina C Betz
Dowling-Degos disease (DDD) is an autosomal-dominant disorder of skin pigmentation associated with mutations in keratin 5 (KRT5), protein O-fucosyltransferase 1 (POFUT1), or protein O-glucosyltransferase 1 (POGLUT1). Here, we have identified 6 heterozygous truncating mutations in PSENEN, encoding presenilin enhancer protein 2, in 6 unrelated patients and families with DDD in whom mutations in KRT5, POFUT1, and POGLUT1 have been excluded. Further examination revealed that the histopathologic feature of follicular hyperkeratosis distinguished these 6 patients from previously studied individuals with DDD...
March 13, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28269784/a-novel-psen1-k311r-mutation-discovered-in-chinese-families-with-late-onset-alzheimer-s-disease-affects-amyloid-%C3%AE-production-and-tau-phosphorylation
#7
Jing Dong, Wei Qin, Cuibai Wei, Yi Tang, Qi Wang, Jianping Jia
BACKGROUND: Presenilin-1 (PSEN1) is the most frequently mutated gene in familial Alzheimer's disease (AD), whereas only several novel mutations have been reported in China and functional studies were seldom conducted. OBJECTIVE: We describe a novel PSEN1 K311R mutation in two Chinese families with late-onset AD and its functional impact on amyloid-β protein precursor (AβPP) processing and tau phosphorylation. METHODS: The mutation was detected by direct sequencing of PSEN1 exon 9...
2017: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/28266222/conditional-depletion-of-hippocampal-brain-derived-neurotrophic-factor-exacerbates-neuropathology-in-a-mouse-model-of-alzheimer-s-disease
#8
David J Braun, Sergey Kalinin, Douglas L Feinstein
Damage occurring to noradrenergic neurons in the locus coeruleus (LC) contributes to the evolution of neuroinflammation and neurodegeneration in a variety of conditions and diseases. One cause of LC damage may be loss of neurotrophic support from LC target regions. We tested this hypothesis by conditional unilateral knockout of brain-derived neurotrophic factor (BDNF) in adult mice. To evaluate the consequences of BDNF loss in the context of neurodegeneration, the mice harbored familial mutations for human amyloid precursor protein and presenilin-1...
March 2017: ASN Neuro
https://www.readbyqxmd.com/read/28193235/dynamic-presenilin-1-and-synaptotagmin-1-interaction-modulates-exocytosis-and-amyloid-%C3%AE-production
#9
Katarzyna Marta Zoltowska, Masato Maesako, Iryna Lushnikova, Shuko Takeda, Laura J Keller, Galina Skibo, Bradley T Hyman, Oksana Berezovska
BACKGROUND: Alzheimer's disease (AD)-linked protein, presenilin 1 (PS1), is present at the synapse, and the knock-out of presenilin in mice leads to synaptic dysfunction. On the other hand, synaptic activity was shown to influence PS1-dependent generation of distinct amyloid β (Aβ) species. However, the precise nature of these regulations remains unclear. The current study reveals novel role of PS1 at the synapse, and deciphers how PS1 and synaptic vesicle-associated protein, synaptotagmin 1 (Syt1) modulate each other functions in neurons via direct activity-triggered interaction...
February 13, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28181072/interactions-of-mitochondria-metabolism-and-calcium-regulation-in-alzheimer-s-disease-a-calcinist-point-of-view
#10
Gary E Gibson, Ankita Thakkar
Decades of research suggest that alterations in calcium are central to the pathophysiology of Alzheimer's Disease (AD). Highly reproducible changes in calcium dynamics occur in cells from patients with both genetic and non-genetic forms of AD relative to controls. The most robust change is an exaggerated release of calcium from internal stores. Detailed analysis of these changes in animal and cell models of the AD-causing presenilin mutations reveal robust changes in ryanodine receptors, inositol tris-phosphate receptors, calcium leak channels and store activated calcium entry...
February 8, 2017: Neurochemical Research
https://www.readbyqxmd.com/read/28165225/initial-substrate-binding-of-%C3%AE-secretase-the-role-of-substrate-flexibility
#11
Shu Li, Wan Zhang, Wei Han
γ-Secretase cleaves transmembrane domains (TMD) of amyloid precursor protein (APP), producing pathologically relevant amyloid-β proteins. Initial substrate binding represents a key step of the γ-secretase cleavage whose mechanism remains elusive. Through long timescale coarse-grained and atomic simulations, we have found that the APP TMD can bind to the catalytic subunit presenilin 1 (PS1) on an extended surface covering PS1's TMD2/6/9 and PAL motif that are all known to be essential for enzymatic activity...
February 6, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28152299/development-of-a-reporter-system-for-in-vivo-monitoring-of-%C3%AE-secretase-activity-in-drosophila
#12
Young Gi Hong, Seyun Roh, Donggi Paik, Sangyun Jeong
The γ-secretase complex represents an evolutionarily conserved family of transmembrane aspartyl proteases that cleave numerous type-I membrane proteins, including the β-amyloid precursor protein (APP) and the receptor Notch. All known rare mutations in APP and the γ-secretase catalytic component, presenilin, which lead to increased amyloid βpeptide production, are responsible for early-onset familial Alzheimer's disease. β-amyloid protein precursor-like (APPL) is the Drosophila ortholog of human APP. Here, we created Notch- and APPL-based Drosophila reporter systems for in vivo monitoring of γ-secretase activity...
January 2017: Molecules and Cells
https://www.readbyqxmd.com/read/28132667/pathogenic-ps1-phosphorylation-at-ser367
#13
Masato Maesako, Jana Horlacher, Katarzyna M Zoltowska, Ksenia V Kastanenka, Eleanna Kara, Sarah Svirsky, Laura J Keller, Xuejing Li, Bradley T Hyman, Brian J Bacskai, Oksana Berezovska
The high levels of serine (S) and threonine (T) residues within the Presenilin 1 (PS1) N-terminus and in the large hydrophilic loop region suggest that the enzymatic function of PS1/γ-secretase can be modulated by its 'phosphorylated' and 'dephosphorylated' states. However, the functional outcome of PS1 phosphorylation and its significance for Alzheimer's disease (AD) pathogenesis is poorly understood. Here, comprehensive analysis using FRET-based imaging reveals that activity-driven and Protein Kinase A-mediated PS1 phosphorylation at three domains (domain 1: T74, domain 2: S310 and S313, domain 3: S365, S366, and S367), with S367 being critical, is responsible for the PS1 pathogenic 'closed' conformation, and resulting increase in the Aβ42/40 ratio...
January 30, 2017: ELife
https://www.readbyqxmd.com/read/28131463/very-early-onset-sporadic-alzheimer-s-disease-with-a-de-novo-mutation-in-the-psen1-gene
#14
Fan Lou, Xiaoguang Luo, Ming Li, Yan Ren, Zhiyi He
We report a 22-year onset age man diagnosed with rapidly progressing early-onset Alzheimer's disease with predominant extrapyramidal symptoms as the initial presenting symptoms and V391G mutation in presenilin 1 gene (PSEN1) was founded. The unaffected parents of the proband are not carriers of the mutation but have histories of extrapyramidal diseases, suggesting de novo origin of V391G mutation. The Val391Gly variation widens the number of PSEN1 mutations responsible for early-onset Alzheimer's disease with extrapyramidal phenotype and would help to establish a functional map of presenilin 1 protein architecture...
January 6, 2017: Neurobiology of Aging
https://www.readbyqxmd.com/read/28120269/presenilin-2-deficiency-facilitates-a%C3%AE-induced-neuroinflammation-and-injury-by-upregulating-p2x7-expression
#15
Juliang Qin, Xiaoyu Zhang, Ziqiang Wang, Jinju Li, Zhen Zhang, Liangcai Gao, Hua Ren, Min Qian, Bing Du
Accumulating evidence suggests that β-amyloid (Aβ)-induced neuroinflammation plays a prominent and early role in Alzheimer's disease (AD). In this study, we demonstrated that Presenilin 2 (PS2) deficiency facilitates Aβ-induced neuroinflammation and injury by upregulating P2X7 expression both in vitro and in vivo. PS2 knockout mice demonstrated increased cognitive impairments and cerebral injury. PS2 deficiency increased the expression of P2X7 both in neurons and microglial cells. Furthermore, extracellular ATP also increased in both Aβ-treated and untreated PS2 knockout microglial cells...
January 23, 2017: Science China. Life Sciences
https://www.readbyqxmd.com/read/28120208/huannao-yicong-formula-regulates-%C3%AE-secretase-activity-through-aph-1-and-pen-2-gene-ragulation-pathways-in-hippocampus-of-app-ps1-double-transgenic-mice
#16
Zhi-Yong Wang, Jian-Gang Liu, Yun Wei, Mei-Xia Liu, Qi Wang, Lin Liang, Hui-Min Yang, Hao Li
OBJECTIVE: To observe the effects of Huannao Yicong Formula (, HYF) on learning and memory and it's regulating effect on γ-secretase related anterior pharynx defective 1 (APH-1), presenilin enhancer-2 (PEN-2) signaling pathway, so as to discuss and further clarify the mechanism of HYF on Alzheimer's disease. METHODS: Sixty APP/PS1 transgenic mice, randomly allocated into 4 groups, the model group, the donepezil group (0.65 mg/kg), HYF low-dose group (HYF-L, 5.46 g/kg) and HYF high-dose group (HYF-H, 10...
January 24, 2017: Chinese Journal of Integrative Medicine
https://www.readbyqxmd.com/read/28096459/zinc-and-copper-differentially-modulate-amyloid-precursor-protein-processing-by-%C3%AE-secretase-and-amyloid-%C3%AE-peptide-production
#17
Hermeto Gerber, Fang Wu, Mitko Dimitrov, Guillermo M Garcia Osuna, Patrick C Fraering
Recent evidence suggests involvement of biometal homeostasis in the pathological mechanisms in Alzheimer's disease (AD). For example, increased intracellular copper or zinc has been linked to a reduction in secreted levels of the AD-causing amyloid-β peptide (Aβ). However, little is known about whether these biometals modulate the generation of Aβ. In the present study we demonstrate in both cell-free and cell-based assays that zinc and copper regulate Aβ production by distinct molecular mechanisms affecting the processing by γ-secretase of its Aβ precursor protein substrate APP-C99...
March 3, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28068334/two-paralogous-tetraspanins-tsp-12-and-tsp-14-function-with-the-adam10-metalloprotease-sup-17-to-promote-bmp-signaling-in-caenorhabditis-elegans
#18
Lin Wang, Zhiyu Liu, Herong Shi, Jun Liu
The highly conserved bone morphogenetic protein (BMP) signaling pathway regulates many developmental and homeostatic processes. While the core components of the BMP pathway have been well studied, much research is needed for understanding the mechanisms involved in the precise spatiotemporal control of BMP signaling in vivo. Here, we provide evidence that two paralogous and evolutionarily conserved tetraspanins, TSP-12 and TSP-14, function redundantly to promote BMP signaling in C. elegans. We further show that the ADAM10 (a disintegrin and metalloprotease 10) ortholog SUP-17 also functions to promote BMP signaling, and that TSP-12 can bind to and promote the cell surface localization of SUP-17...
January 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28065657/mapping-the-binding-site-of-bms-708163-on-%C3%AE-secretase-with-cleavable-photoprobes
#19
Natalya Gertsik, Christopher W Am Ende, Kieran F Geoghegan, Chuong Nguyen, Paramita Mukherjee, Scot Mente, Uthpala Seneviratne, Douglas S Johnson, Yue-Ming Li
γ-Secretase, a four-subunit transmembrane aspartic proteinase, is a highly valued drug target in Alzheimer's disease and cancer. Despite significant progress in structural studies, the respective molecular mechanisms and binding modes of γ-secretase inhibitors (GSIs) and modulators (GSMs) remain uncertain. Here, we developed biotinylated cleavable-linker photoprobes based on the BMS-708163 GSI to study its interaction with γ-secretase. Comparison of four cleavable linkers indicated that the hydrazine-labile N-1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl (Dde) linker was cleaved most efficiently to release photolabeled and affinity-captured presenilin-1 (PS1), the catalytic subunit of γ-secretase...
January 19, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28065273/screening-and-characterization-strategies-for-nanobodies-targeting-membrane-proteins
#20
S Veugelen, M Dewilde, B De Strooper, L Chávez-Gutiérrez
The study of membrane protein function and structure requires their successful detection, expression, solubilization, and/or reconstitution, which poses a challenging task and relies on the availability of suitable tools. Several research groups have successfully applied Nanobodies in the purification, as well as the functional and structural characterization of membrane proteins. Nanobodies are small, single-chain antibody fragments originating from camelids presenting on average a longer CDR3 which enables them to bind in cavities and clefts (such as active and allosteric sites)...
2017: Methods in Enzymology
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