Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: UMLS:C0027819 (neuroblastoma)
27,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pathogenic mutations in presenilin 1 (PS1) are associated with approximately 50% of early-onset familial Alzheimer disease. PS1 is endoproteolytically cleaved to yield a 30-kDa N-terminal fragment (NTF) and an 18-kDa C-terminal fragment (CTF). Using COS7 cells transfected with human PS1, we have found that phorbol 12, 13-dibutyrate and forskolin increase the state of phosphorylation of serine residues of the human CTF. Phosphorylation of the human CTF resulted in a shift in electrophoretic mobility from a single major species of 18 kDa to a doublet of 20-23 kDa. This mobility shift was also observed with human PS1 that had been transfected into mouse neuroblastoma (N2a) cells. Treatment of the phosphorylated CTF doublet with phage lambda protein phosphatase eliminated the 20- to 23-kDa doublet while enhancing the 18-kDa species, consistent with the interpretation that the electrophoretic mobility shift was due to the addition of phosphate to the 18-kDa species. The NTF and CTF eluted from a gel filtration column at an estimated mass of over 100 kDa, suggesting that these fragments exist as an oligomerized species. Upon phosphorylation of the PS1 CTF, the apparent mass of the NTF- or CTF-containing oligomers was unchanged. Thus, the association of PS1 fragments may be maintained during cycles of phosphorylation/dephosphorylation of the PS1 CTF.
...
PMID:Evidence for phosphorylation and oligomeric assembly of presenilin 1. 914 95

The recently identified Alzheimer's disease-associated presenilin 1 and 2 (PS1 and PS2) genes encode two homologous multi membrane-spanning proteins. Rabbit antibodies to the N-terminal domain of PS1 detected PS1 in human neuroblastoma SH-SY5Y wild type and PS1 transfectants (SY5Y-PS1) as well as in mouse P19, in CHO-K1 and CHO-APP770 transfected cells, in rat cerebellar granule and hippocampal neurons, and astrocytes. Immunoblotting detected full-length protein of 50 kDa, and a major presumptive cleavage product of 30 kDa. The immunofluorescence pattern resembled labeling of the endoplasmic reticulum-Golgi intermediate compartment (ERGIC) marker protein ERGIC-53. PS1 distribution showed slight condensation after brefeldin A and more marked condensation after incubation of cells at 16 degrees C, characteristic of the ERGIC compartment. Double labeling showed colocalization of ERGIC-53 with PS1 in the SY5Y-PS1 cells. PS1 labeling of SY5Y-PS1 and P19 cells showed overlap of the cis-Golgi marker p210 and colocalization with p210 after brefeldin A which causes redistribution of p210 to the ERGIC. Expression of PS1 did not change in level or cellular distribution during development of neurons in culture. Double labeling for the amyloid precursor protein (APP) and PS1 on SY5Y-PS1 cells and CHO-APP770 cells showed some overlap under control conditions. These results indicate that PS1 is a resident protein of the ERGIC and could be involved in trafficking of proteins, including APP, between the ER and Golgi compartments.
...
PMID:Alzheimer's disease-associated presenilin 1 in neuronal cells: evidence for localization to the endoplasmic reticulum-Golgi intermediate compartment. 933 59

Mutations in the presenilin 1 (PS1) and presenilin 2 (PS2) genes are associated with early-onset autosomal dominant familial Alzheimer's disease, and the gene products are endoproteolytically processed to yield N-terminal fragments (NTF) and C-terminal fragments (CTF). We have studied the cleavage site of the PS2 protein in stably transfected human neuroblastoma cells. The 23 kD PS2-CTF was isolated by a combination of anion exchange chromatography and affinity chromatography and directly sequenced. The N-terminus of the PS2-CTF started at residue 307, which indicated that the cleavage occurs between Lys306 and Leu307 in the proximal portion of the large hydrophilic loop. This site is close to the cleavage positions observed in the PS1 protein.
...
PMID:Determination of a cleavage site of presenilin 2 protein in stably transfected SH-SY5Y human neuroblastoma cell lines. 939 34

Because distinct mutations in presenilin 1 and presenilin 2 are a major cause of early-onset familial Alzheimer's disease, we generated four monoclonal antibodies for the identification, localization, and investigation of presenilins in various cell lines and tissues from patients and controls. We show that these antibodies are specific for the N- and C-terminal domains of human presenilin 1 and presenilin 2. They recognize presenilin full-length proteins and their approximately 28-35 kDa N-terminal fragments and approximately 18-20 kDa C-terminal fragments. None of the antibodies showed cross-reaction in their specific detection ability. We demonstrated that presenilin 1 and presenilin 2 are proteolytically processed in human glioma cell lines, transfected and untransfected human neuroblastoma SH-SY5Y cells, COS-7 cells, rat cerebellar neuronal ST15 cells, mouse and human brain. Remarkably, we observed that presenilin 2 is alternatively cleaved during apoptosis, producing smaller C-terminal fragments. By analyzing the subcellular distribution of presenilins, we found reticular and fine vesicular staining throughout the cell bodies. In addition, staining of Golgi compartments and the perinuclear envelope was observed. Alzheimer's disease brain showed strong immunoreactivity of presenilin 1 in reactive astrocytes and senile plaques. This high expression of presenilin 1 may explain the increased production and accumulation of the amyloid-beta peptide in patients with sporadic Alzheimer's disease in the absence of familial presenilin mutation.
...
PMID:Analysis of presenilin 1 and presenilin 2 expression and processing by newly developed monoclonal antibodies. 1034 Jul 48

Mutations in presenilin 1 (PS1) and presenilin 2 (PS2) are the most common genetic factors underlying the development of early-onset familial Alzheimer's disease (FAD). To investigate the pathogenic mechanism of PS1 mutations linked to FAD, we established inducible mouse neuroblastoma (Neuro 2a) cell lines expressing the human wild-type (wt) or mutated PS1(M146L or deltaexon 10) under the control of the Lac repressor. Using this inducible PS1 system, the influence of PS1 mutations on the generation of endogenous murine Abeta species was assessed using a highly sensitive immunoblotting technique. The induction of mutated PS1 resulted in an increase in the extra- and intracellular levels of two distinct Abeta species ending at residue 42, Abeta1-42 and its N-terminally truncated variant(s), Abetax-42. In addition, the intracellular generation of these Abeta42 species was completely blocked by brefeldin A. In contrast, it exhibited differential sensitivities to monensin such that there was an increased accumulation of intracellular Abetax-42 but an inhibition of intracellular Abeta1-42 generation. These data strongly suggest that Abetax-42 is generated in a proximal Golgi compartment, whereas Abeta1-42 is generated in a distal Golgi and/or a post-Golgi compartment. Thus, it appears that PS1 mutations enhance the degree of 42-specific gamma-secretase cleavage which occurs (i) in the ER or the early Golgi apparatus prior to gamma-secretase cleavage, or (ii) in the distinct sites where Abetax-42 and Abeta1-42 are generated. To date, the site of Abeta42 generation has not been firmly established. Our data provide new information regarding the site of Abeta42 generation mediated by the FAD-linked mutant PS1.
...
PMID:Implications of presenilin 1 mutations in Alzheimer's disease. 1036 Jun 83

Mutations in the presenilin 1 ( PSEN1 ) gene have been implicated in 18-50% of autosomal dominant cases with early-onset Alzheimer's disease (EOAD). Also, PSEN1 has been suggested as a potential risk gene in late-onset AD cases. We recently showed genetic association in a population-based study of EOAD, pointing to the 5' regulatory region of PSEN1. In this study we systematically screened 3.5 kb of the PSEN1 upstream region and found four novel polymorphisms. Genetic analysis confirmed association of two polymorphisms with increased risk for EOAD. In addition, we detected two different mutations in EOAD cases at-280 and-2818 relative to the transcription initiation site in exon 1A of PSEN1. Analysis of the mutant and wild-type-280 variants using luciferase reporter gene expression in transiently transfected neuroblastoma cells showed a 30% decrease in transcriptional activity for the mutant-280G PSEN1 promoter variant compared with the wild-type variant-280C. Our data suggest that the increased risk for EOAD associated with PSEN1 may result from genetic variations in the regulatory region leading to altered expression levels of the PSEN1 protein.
...
PMID:Genetic variability in the regulatory region of presenilin 1 associated with risk for Alzheimer's disease and variable expression. 1065 40

Mutations in the presenilin 1 and 2 (PS1 and PS2) genes cause most cases of early onset Alzheimer's disease. The genes encode two homologous multipass membrane proteins. Since the endogenous expression of PS2 has been poorly analyzed to date, we studied PS2 expression and localization in cultured human neuroblastoma cells and mouse neuronal cells. PS2 was mainly detected as a full-length protein of about 52 kDa in these cells and in brain, in contrast to PS1 that is mainly detected as endoproteolytic N-terminal and C-terminal fragments. Using immunofluorescence we found that like PS1, PS2 colocalized with markers of the endoplasmic reticulum-Golgi intermediate compartment, ERGIC-53 and beta-COP. Double labeling for PS1 and PS2 indicated that both proteins are colocalized in neuroblastoma SH-SY5Y cells. To study PS2 expression during differentiation, mouse embryonic carcinoma P19 cells were treated with retinoic acid. We found minimal PS2 expression in undifferentiated cells, an increase from day 2, and a maximum at day 8 after treatment. PS1 expression remained constant during this period. The differential expression of PS1 and PS2 within the P19 cells following retinoic acid treatment indicates different utilization or temporal requirements for these proteins during neuronal differentiation.
...
PMID:Presenilin 2 expression in neuronal cells: induction during differentiation of embryonic carcinoma cells. 1069 35

Mutations in the presenilin 1 (PS1) gene are associated with autosomal dominant, early-onset, familial Alzheimer's disease and result in increased release of the hyperaggregatable 42-amino acid form of the amyloid beta-peptide (A(beta)42). To determine which subcellular compartments are potential source(s) of released Abeta42, we compared the levels and spatial segregation of intracellular A(beta)40 and A(beta)42 peptides between N2a neuroblastoma cells doubly transfected with the "Swedish" familial Alzheimer's disease-linked amyloid precursor protein variant and either wild-type PS1 (PS1(wt)) or familial Alzheimer's disease-linked delta9 mutant PS1 (PS1delta9). As expected, PS1delta9-expressing cells had dramatically higher levels of intracellular Abeta42 than did cells expressing PS1wt. However, the highest levels of A(beta)42 colocalized not with endoplasmic reticulum or Golgi markers but with rab8, a marker for trans-Golgi network (TGN)-to-plasma membrane (PM) transport vesicles. We show that PS1 mutants are capable of causing accumulation of A(beta)42 in late compartments of the secretory pathway, generating there a readily releasable source of A(beta)42. Our findings indicate that PS1 "bioactivity" localizes to the vicinity of the TGN and/or PM and reconcile the apparent discrepancy between the preponderant concentration of PS1 protein in proximal compartments of the secretory pathway and the recent findings that PS1 "bioactivity" can control gamma-secretase-like processing of another transmembrane substrate, Notch, at or near the PM.
...
PMID:Mutant presenilin 1 increases the levels of Alzheimer amyloid beta-peptide Abeta42 in late compartments of the constitutive secretory pathway. 1080 Sep 30

Presenilins (PSs) are mutated in a majority of familial Alzheimer disease (FAD) cases. Mutated PSs may cause FAD by a number of pro-apoptotic mechanisms, or by regulating gamma-secretase activity, a protease involved in beta-amyloid precursor protein processing to the neurotoxic beta-amyloid peptide. Besides their normal endoproteolytic processing, PSs are substrates for caspases, being cleaved to alternative N-terminal and C-terminal fragments. So far little is known about the role of PSs cleavage in the apoptotic machinery. Here, we used SH-SY5Y neuroblastoma cells stably transfected with wild-type or exon 9 deleted presenilin 1 (PS1) in a time-course study after the exposure to the calcium ionophore A23187. During and after exposure to A 23187, intracellular calcium levels were higher in exon 9 deleted PS1 cells as compared with non-transfected and wild-type PS1 transfected cells. Cell death and the enrichment of apoptotic cells after A23187 exposure were increased by overexpression of exon 9 deleted PS1 as compared with the control cell lines. Wild-type PS1 cells were compared with exon 9 deleted PS1 cells and the temporal relationship between PS1 and other caspase substrates cleavages was analyzed. Exon 9 deleted PS1 cells exhibited a higher caspase-3 activation and a greater cleavage of PS1 and poly(ADP-ribose) polymerase (PARP) compared with wild-type PS1 cells. Exon 9 deleted PS1 cleavage occurred earlier than other caspase substrate cleavages (i.e., PARP and gelsolin), simultaneous with minimum detectable caspase-3 activation. Therefore, alternative cleavage of PS1 may play an important role for the regulation of the proteolytic cascade activated during apoptosis.
...
PMID:Caspase cleavage of exon 9 deleted presenilin-1 is an early event in apoptosis induced by calcium ionophore A 23187 in SH-SY5Y neuroblastoma cells. 1159 9

We describe a Polish family with Alzheimer's disease in some of its members. Two sisters were observed and examined--also neuropathologically in the Institute of Psychiatry and Neurology in Warsaw. The disease onset was in our patients at 32 and 33 years. The first symptoms were memory loss and disorientation. Later on myoclonus and extrapyramidal stiffness were noted in both cases. Neurovisualizing examinations performed in both sisters showed diffuse brain atrophy. The symptoms increased rapidly and in short time (several months) the patients became mute and bedbound. They died at age 35 and 37 years. We were informed that the father of the patients suffered from very similar illness and died at age of 37 years and their older brother had the some symptoms and died at the age of 28 years. Post-mortem brain examination disclosed in the both hospitalized cases diffuse atrophy of the cerebral hemispheres, particularly severe in the temporal lobes. Microscopically senile plaques of various types were found in the cortex. The density of the plaques was very high but Alzheimer's fibrillary degeneration was found occasionally only. The amyloid burden in cortex of the examined brains, estimated as the measure of parenchymal amyloidosis beta, was two to six-fold higher in most areas compared with changes in sporadic AD and Down-syndrome cases. DNA was isolated from blood and tissue of both cases and from blood of their 8 children as well. In both patients mutation in presenilin 1 (PS1) gene of Prol 117 Leu was found and it was discovered that 4 persons of their progeniture were carriers of this mutation. The described mutation causes one of the earliest so far reported onset and death in FAD kindreds. Presenilin isolated from both cases and transfected into cultures of murine neuroblastoma and human kidneys provoked production of beta amyloid with increased A-beta 42/40 ratio.
...
PMID:[Familial Alzheimer's disease connected with mutation in presenilin gene 1 (P117L)]. 1159 21


1 2 3 4 5 Next >>

---