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BBA - Molecular Basis of Disease (v.1812, #12)
Oral colonization by Streptococcus mutans and caries development is reduced upon deletion of carbonic anhydrase VI expression in saliva by David J. Culp; Bently Robinson; Seppo Parkkila; Pei-wen Pan; Melanie N. Cash; Helen N. Truong; Thomas W. Hussey; Sarah L. Gullett (pp. 1567-1576).
Carbonic anhydrase VI (CA VI), encoded by type A transcripts of the gene Car6, is a secretory product of salivary glands and is found in the enamel pellicle. Because higher caries prevalence is associated with lower salivary concentrations of CA VI in humans, we tested whether CA VI protects enamel surfaces from caries induced by Streptococcus mutans, using Car6−/− mice, in which salivary CA VI expression is absent. We detected aberrant Car6 type A transcripts in Car6 −/− mice, likely targets for nonsense-mediated mRNA decay. Expression of the intracellular stress-induced isoform of CA VI encoded by type B transcripts was restricted to parotid and submandibular glands of wild type mice. The salivary function of Car6 −/− mice was normal as assessed by the histology and protein/glycoprotein profiles of glands, salivary flow rates and protein/glycoprotein compositions of saliva. Surprisingly, total smooth surface caries and sulcal caries in Car6 −/− mice were more than 6-fold and 2-fold lower than in wild type mice after infection with S. mutans strain UA159. Recoveries of S. mutans and total microbiota from molars were also lower in Car6 −/− mice. To explore possible mechanisms for increased caries susceptibility, we found no differences in S. mutans adherence to salivary pellicles, in vitro. Interestingly, higher levels of Lactobacillus murinus and an unidentified Streptococcus species were cultivated from the oral microbiota of Car6 −/− mice. Collective results suggest salivary CA VI may promote caries by modulating the oral microbiota to favor S. mutans colonization and/or by the enzymatic production of acid within plaque.► All major salivary glands express Car6 type A transcripts (secretory CA VI). ► Car6 type B mRNA (intracellular CA VI) are expressed selectively in major glands. ► Deletion of both CA VI isoforms has no apparent affects on salivary function. ► The absence of secretory CA VI in saliva is associated with reduced caries in mice. ► Car6 KO mice have altered oral microbiota that may antagonize Streptococcus mutans.
Keywords: Abbreviations; CA VI; carbonic anhydrase alpha, isozyme 6; car6; carbonic anhydrase 6 gene; CHOP; ER stress-related transcription factor C/EBP homologous protein; neo; neomycin; TK; thymidine kinase; SMG; submandibular gland; SLG; sublingual glandCarbonic anhydrase; Saliva; Streptococcus mutans; Oral colonization; Nonsense-mediated decay; Knockout mice
Molecular properties of TAR DNA binding protein-43 fragments are dependent upon its cleavage site by Yoshiaki Furukawa; Kumi Kaneko; Nobuyuki Nukina (pp. 1577-1583).
Aggregation of TAR DNA binding protein-43 (TDP-43) is a hallmark feature of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Under pathogenic conditions, abnormal cleavage of TDP-43 produces the phosphorylated C-terminal fragments (CTFs), which are enriched in neuronal inclusions; however, molecular properties of those TDP-43 fragments remain to be characterized. Here we show distinct degrees of solubility and phosphorylation among fragments truncated at different sites of TDP-43. Truncations were tested mainly within a second RNA recognition motif (RRM2) of TDP-43; when the truncation site was more C-terminal in an RRM2 domain, a TDP-43 CTF basically became less soluble and more phosphorylated in differentiated Neuro2a cells. We also found that cleavage at the third β-strand in RRM2 leads to the formation of SDS-resistant soluble oligomers. Molecular properties of TDP-43 fragments thus significantly depend upon its cleavage site, which might reflect distinct molecular pathologies among sub-types of TDP-43 proteinopathies.► Cleavage-site-dependent properties of TDP-43 C-terminal fragments (CTFs). ► Four distinct types of TDP-43 CTFs exist based upon difference in its insolubility. ► Phosphorylation pattern is also distinct among different types of TDP-43 CTFs. ► TDP-43 pathologies may be diversified by numbers of potential cleavage sites.
Keywords: Abbreviations; TDP-43; TAR DNA binding protein-43; CTF; C-terminal fragment; RRM2; 2nd RNA recognition motif in TDP-43; ALS; amyotrophic lateral sclerosis; FTLD; frontotemporal lobar degenerationTAR DNA binding protein-43; Protein aggregation; Amyotrophic lateral sclerosis; Frontotemporal lobar degeneration
Calcium channel blocking as a therapeutic strategy for Alzheimer's disease: The case for isradipine by Thimmappa S. Anekonda; Joseph F. Quinn (pp. 1584-1590).
Alzheimer's disease is the most devastating neurodegenerative disorder in the elderly, yet treatment options are severely limited. The drug development effort to modify Alzheimer's disease pathology by intervention at beta amyloid production sites has been largely ineffective or inconclusive. The greatest challenge has been to identify and define downstream mechanisms reliably predictive of clinical symptoms. Beta amyloid accumulation leads to dysregulation of intracellular calcium by plasma membrane L-type calcium channels located on neuronal somatodendrites and axons in the hippocampus and cortex. Paradoxically, L-type calcium channel subtype Cav1.2 also promotes synaptic plasticity and spatial memory. Increased intracellular calcium modulates amyloid precursor protein processing and affects multiple downstream pathways including increased hyperphosphorylated tau and suppression of autophagy. Isradipine is a Federal Drug Administration-approved dihydropyridine calcium channel blocker that binds selectively to Cav1.2 in the hippocampus. Our studies have shown that isradipine in vitro attenuates beta amyloid oligomer toxicity by suppressing calcium influx into cytoplasm and by suppressing Cav1.2 expression. We have previously shown that administration of isradipine to triple transgenic animal model for Alzheimer's disease was well-tolerated. Our results further suggest that isradipine became bioavailable, lowered tau burden, and improved autophagy function in the brain. A better understanding of brain pharmacokinetics of calcium channel blockers will be critical for designing new experiments with appropriate drug doses in any future clinical trials for Alzheimer's disease. This review highlights the importance of Cav1.2 channel overexpression, the accumulation of hyperphosphorylated tau and suppression of autophagy in Alzheimer's disease and modulation of this pathway by isradipine.Display Omitted► Aβ neurotoxicity leads to intracellular calcium influx and vice versa. ► Intracellular calcium influx occurs via Cav1.2 channels. ► Calcium influx further leads to increased hyperphosphrylated tau and autophagy dysfunction. ► L-type voltage-gated calcium channel blockers prevent neurotoxicity associated with intracellular Aβ and calcium. ► Isradipine appears to be a potent calcium channel blocker.
Keywords: Autophagy; Beta amyloid; Bioavailability; Tau
Low molecular weight heparin downregulates tissue factor expression and activity by modulating growth factor receptor-mediated induction of nuclear factor-κB by Camille Ettelaie; Donna Fountain; Mary Elizabeth W. Collier; Azza M. ElKeeb; Yu Pei Xiao; Anthony Maraveyas (pp. 1591-1600).
Treatment of cancer patients with low molecular weight heparin (LMWH) appears to have beneficial effects. In this study, the influence of low molecular weight heparin (LMWH) on tissue factor (TF) expression and activity in five cell lines from various tissues was analysed and explored. Incubation of cells with LMWH (0–2000μg/ml) resulted in the downregulation of TF mRNA expression which was both LMWH concentration-dependent and time-dependent. Downregulation of TF was also measured as decreased cellular TF antigen and activity. Consistently, incubation of cells with LMWH suppressed the nuclear localisation and the transcriptional activity of NFκB. Decreased TF mRNA was largely achievable by incubating the cells with an NFκB inhibitor alone whilst incubation with betulinic acid to activate NFκB reversed the inhibitory influence of LMWH. Cells were also incubated with a range of concentrations of EGF (0–10ng/ml), bFGF (0–20ng/ml) or VEGF (0–4ng/ml) in the presence or absence of LMWH (200μg/ml) for 24h and TF antigen measured. Inclusion of LMWH reduced TF expression in response to EGF, bFGF or VEGF but TF expression was partially restored by increasing concentrations of the growth factors. We conclude that LMWH downregulates TF expression in vitro through a mechanism that involves interference with the function of growth factors which in turn is mediated through the downregulation of the transcriptional activity of NFκB. This mechanism may also explain some of the beneficial influences attributed to LMWH therapy in the treatment of cancer patients.► Downregulation of TF by LMWH in vitro was shown for the first time and a coherent mechanism for TF suppression identified. ► The mechanism involves the prevention of nuclear translocation of NFκB by interfering with growth factor receptor function. ► LMWH downregulates cellular TF antigen/activity gradually since cellular TF reservoirs are depleted at differing rates. ► The study explains the reported suppression of TF in vivo by LMWH at therapeutic doses. ► A new RT-PCR-based procedure for the absolute quantification of TF mRNA is developed and described.
Keywords: Abbreviations; TF; tissue factor; LMWH; low molecular weight heparin; NFκB; nuclear factor κB; EGF; epidermal growth factor; bFGF; basic fibroblast growth factor; VEGF; vascular endothelial growth factorTissue factor; Low molecular weight heparin; NFκB; Growth factor receptor; Cancer cell lines
Gut barrier dysfunction in the Apc Min/+ mouse model of colon cancer cachexia by Melissa J. Puppa; James P. White; Shuichi Sato; Mark Cairns; John W. Baynes; James A. Carson (pp. 1601-1606).
Background: The Apc Min/+ mouse, an animal model of colorectal cancer and cachexia, has a heterologous mutation in the Apc tumor suppressor gene, predisposing the mouse to intestinal and colon tumor development. This mouse develops intestinal polyps by ~4weeks of age, and loses body weight gradually between ~14 and ~20weeks of age. The strengths of this cachexia model derive from several features that mimic human cancer, including a gradual increase in tumor burden, chronic inflammation, and anemia. Little is known about the role of gut barrier dysfunction and endotoxemia in the development of cancer cachexia. We sought to determine how gut permeability and resultant endotoxemia change with the progression of cachexia. Methods: Intestinal gut barrier integrity was assessed by permeability to FITC-dextran (MWav=4000kDa; FD4). Plasma glucose and triglycerides were measured by enzymatic assays, IL-6 by enzyme-linked immunosorbent assay, and endotoxin by the limulus amoebocyte assay. Body temperature was measured using a rectal probe. Results: Progression of cachexia was accompanied by development of gut barrier dysfunction (permeability to FD4), hypertrophy of mesenteric lymph nodes, and an increase in plasma endotoxin concentration. Changes in blood glucose and glucose tolerance, plasma IL-6, triglycerides, and body temperature were characteristic of endotoxemia. Conclusion: We propose a role for gut barrier dysfunction (GBD) and subsequent endotoxemia in the development of inflammation and progression of cachexia in the Apc Min/+ mouse.►The Apc Min/+ model of colon cancer cachexia develops endotoxemia and gut barrier dysfunction. ►IL-6 over-expression increases intestinal permeability in Apc Min/+ mice. ►Intestinal permeability correlates with increases in tumor size and Il-6 levels.
Keywords: Cachexia; Colorectal cancer; Endotoxin; Gut barrier dysfunction; Gut permeability; Inflammation
Severe dysfunction of respiratory chain and cholesterol metabolism in Atp7b−/− mice as a model for Wilson disease by Sven W. Sauer; Uta Merle; Silvana Opp; Dorothea Haas; Georg F. Hoffmann; Wolfgang Stremmel; Jürgen G. Okun (pp. 1607-1615).
Wilson disease (WD) is caused by mutations of the WD gene ATP7B resulting in copper accumulation in different tissues. WD patients display hepatic and neurological disease with yet poorly understood pathomechanisms. Therefore, we studied age-dependent (3, 6, 47weeks) biochemical and bioenergetical changes in Atp7b −/− mice focusing on liver and brain. Mutant mice showed strongly elevated copper and iron levels. Age-dependently decreasing hepatic reduced glutathione levels along with increasing oxidized to reduced glutathione ratios in liver and brain of 47weeks old mice as well as elevated hepatic and cerebral superoxide dismutase activities in 3weeks old mutant mice highlighted oxidative stress in the investigated tissues. We could not find evidence that amino acid metabolism or beta-oxidation is impaired by deficiency of ATP7B. In contrast, sterol metabolism was severely dysregulated. In brains of 3week old mice cholesterol, 8-dehydrocholesterol, desmosterol, 7-dehydrocholesterol, and lathosterol were all highly increased. These changes reversed age-dependently resulting in reduced levels of all previously increased sterol metabolites in 47weeks old mice. A similar pattern of sterol metabolite changes was found in hepatic tissue, though less pronounced. Moreover, mitochondrial energy production was severely affected. Respiratory chain complex I activity was increased in liver and brain of mutant mice, whereas complex II, III, and IV activities were reduced. In addition, aconitase activity was diminished in brains of Atp7b −/− mice. Summarizing, our study reveals oxidative stress along with severe dysfunction of mitochondrial energy production and of sterol metabolism in Atp7b −/− mice shedding new light on the pathogenesis of WD. ►Atp7b −/− mice as model for Wilson disease. ►Biochemical and bioenergetical characterization with focus on liver and brain. ►Alteration of anti-oxidative defense. ►Dysregulation of sterol metabolism. ►Dysfunction of mitochondrial energy production by impairment of respiratory chain and decreased aconitase activity.
Keywords: Abbreviations; 7-DHC; 7-Dehydrocholesterol; 8-DHC; 8-Dehydrocholesterol; ESI-MS/MS; Electrospray ionization tandem mass spectrometry; Nitroso-PSAP; 2-Nitroso-5-(N-propyl-3-sulfopropylamino)phenol; ROS; Reactive oxygen species; SOD; Superoxide dismutase; WD; Wilson DiseaseWilson disease; Copper; Respiratory chain; Sterol metabolism; ROS
Proteoglycan degradation by the ADAMTS family of proteinases by Heather Stanton; James Melrose; Christopher B. Little; Amanda J. Fosang (pp. 1616-1629).
Proteoglycans are key components of extracellular matrices, providing structural support as well as influencing cellular behaviour in physiological and pathological processes. The diversity of proteoglycan function reported in the literature is equally matched by diversity in proteoglycan structure. Members of the ADAMTS (A Disintegrin And Metalloproteinase with ThromboSpondin motifs) family of enzymes degrade proteoglycans and thereby have the potential to alter tissue architecture and regulate cellular function. In this review, we focus on ADAMTS enzymes that degrade the lectican and small leucine-rich repeat families of proteoglycans. We discuss the known ADAMTS cleavage sites and the consequences of cleavage at these sites. We illustrate our discussion with examples from the literature in which ADAMTS proteolysis of proteoglycans makes profound changes to tissue function.► Lecticans and SLRPs are proteoglycans that can be degraded by ADAMTS proteinases in vivo. ► ADAMTS enzymes are members of the metzincin family of zinc-dependent proteinases. ► Lecticans bind hyaluronan to help hydrate tissues and confer biomechanical properties. ► SLRPs can act as co-receptors for signalling or depots for growth factor binding. ► ADAMTS cleavage of lecticans and SLRPs can be pathological or physiological.
Keywords: Abbreviations; ADAMTS; A Disintegrin And Metalloproteinase with ThromboSpondin motifs; CS; chondroitin sulphate; DS; dermatan sulphate; ECM; extracellular matrix; G1, G2, G3; first, second and third globular domains of lecticans; HA; hyaluronan; IGD; interglobular domain; KS; keratan sulphate; HS; heparan sulphate; PTR; proteoglycan tandem repeat; MV; mother vessels; SMC; smooth muscle cell; TS; thrombospondinAggrecan; Brevican; Versican; SLRP; Neoepitope
Brain aging, Alzheimer's disease, and mitochondria by Russell H. Swerdlow (pp. 1630-1639).
The relationship between brain aging and Alzheimer's disease (AD) is contentious. One view holds AD results when brain aging surpasses a threshold. The other view postulates AD is not a consequence of brain aging. This review discusses this conundrum from the perspective of different investigative lines that have tried to address it, as well as from the perspective of the mitochondrion, an organelle that appears to play a role in both AD and brain aging. Specific issues addressed include the question of whether AD and brain aging should be conceptually lumped or split, the extent to which AD and brain aging potentially share common molecular mechanisms, whether beta amyloid should be primarily considered a marker of AD or simply brain aging, and the definition of AD itself.► Whether Alzheimer's disease and brain aging are mechanistically linked is contentious. ► New definitions of Alzheimer's disease infer most very elderly individuals have some form of it. ► Beta amyloid homeostasis is regulated by bioenergetic stress. ► Mitochondria may constitute a mechanistic link between Alzheimer's disease and brain aging.
Keywords: Abbreviations; AACD; age-associated cognitive decline; AAMI; age-associated memory impairment; Aβ; beta amyloid; AD; Alzheimer's disease; APP; amyloid precursor protein; BACE; beta secretase; COX; cytochrome oxidase; CSF; cerebrospinal fluid; cybrid; cytoplasmic hybrid; DMN; default mode network; ETC; electron transport chain; FDG; fluorodeoxyglucose; fMRI; functional magnetic resonance imaging; PET; positron emission tomography; PIB; Pittsburgh compound B; MCI; mild cognitive impairment; mtDNA; mitochondrial DNA; PCR; polymerase chain reactionAging; Amyloid; Brain; Dementia; Alzheimer's disease; Mitochondria
Expression of the megalin C-terminal fragment by macrophages during liver fibrogenesis in mice by Pieper-Furst Ursula Pieper-Fürst; Rabea Hall; Sebastian Huss; Katrin Hochrath; Hans-Peter Fischer; Frank Tacke; Ralf Weiskirchen; Frank Lammert (pp. 1640-1648).
The low-density-lipoprotein receptor megalin (LRP2, gp330) is strongly expressed in the kidney, where it is responsible for the resorption of metabolites from primary urine. One of the main ligands is the complex of retinol and retinol binding protein. Megalin has been hypothesized to be part of the retinol storage system in liver. Considering the role of hepatic stellate cells in retinol storage and fibrogenesis we investigated mouse strains that developed different degrees of fibrosis after challenge with CCl4. Immunoblotting revealed the invariable expression of the megalin C-terminal fragment independent of liver damage in all strains. However, only a specific cell population in centrilobular areas of fibrotic livers from DBA/2J mice, which were most susceptible for CCl4-induced fibrogenesis in our study, was stained using megalin-specific antibodies. Double immunostaining indicated that a subset of hepatic macrophages might represent the megalin-expressing cells in fibrotic liver. Fluorescence activated cell sorting based isolation of hepatic macrophages and megalin specific expression analysis demonstrated the transcription of the whole megalin gene in liver macrophages. We argue that megalin might exhibit a proinflammatory effect by the uptake of retinoids in recruited monocytes, which thereby differentiate to liver macrophages and potentiate fibrogenesis by the release of proinflammatory mediators. Otherwise, megalin might be activated in macrophages during advanced fibrogenesis and act as a negative regulator of proinflammatory genes.►Detection of the C-terminal fragment from the multiligand receptor megalin in liver. ►Macrophages express the megalin C-terminal fragment. ►Localization of megalin-positive macrophages in fibrotic areas of murine liver.
Keywords: Carbon tetrachloride; Hepatic fibrosis; LDL receptor related protein 2; LRP2; Macrophages; Megalin C-terminal fragment
Evidence for alteration of calpain/calpastatin system in PBMC of cystic fibrosis patients by Monica Averna; Roberto Stifanese; Roberta De Tullio; Laura Minicucci; Federico Cresta; Serena Palena; Franca Salamino; Sandro Pontremoli; Edon Melloni (pp. 1649-1657).
We are here reporting that in peripheral blood mononuclear cells (PBMC) of patients homozygous for F508del-CFTR the calpain–calpastatin system undergoes a profound alteration. In fact, calpain basal activity, almost undetectable in control PBMC, becomes measurable at a significant extent in cells from cystic fibrosis (CF) patients, also due to a 40–60% decrease in both calpastatin protein and inhibitory activity. Constitutive protease activation in CF patients' cells induces a large accumulation of the mutated cystic fibrosis transmembrane conductance regulator (CFTR) in the 100kD+70kD split forms as well as a degradation of proteins associated to the CFTR complex. Specifically, the scaffolding protein Na+/H+ exchanger 3 regulatory factor-1 (NHERF-1) is converted in two distinct fragments showing masses of 35kD and 20kD, being however the latter form the most represented one, thereby indicating that in CF-PBMC the CFTR complex undergoes a large disorganization. In conclusion, our observations are providing new information on the role of calpain in the regulation of plasma membrane ion conductance and provide additional evidence on the transition of this protease activity from a physiological to a pathological function.► The calpain–calpastatin system is unbalanced in PBMC of F508delCFTR homozygotes. ► NHERF-1 is also degraded in PBMC from CF patients, but not in heterozygous. ► Calpain is responsible for digestion of CFTR associated proteins, including ezrin. ► The rate of this proteolysis is highly increased in PBMC of CF patients. ► The NHERF-1 digestion is the marker of a pathological calpain function.
Keywords: Abbreviations; CF; cystic fibrosis; CFTR; cystic fibrosis transmembrane conductance regulator; NHERF; Na; +; /H; +; exchanger 3 regulatory factor; PBMC; peripheral blood mononuclear cellsCFTR; F508del-CFTR; Ca; 2+; -dependent proteolysis; Calpain; NHERF-1; Ezrin
Cofactors and metabolites as potential stabilizers of mitochondrial acyl-CoA dehydrogenases by Tânia G. Lucas; Bárbara J. Henriques; João V. Rodrigues; Peter Bross; Niels Gregersen; Cláudio M. Gomes (pp. 1658-1663).
Protein misfolding is a hallmark of a number of metabolic diseases, in which fatty acid oxidation defects are included. The latter result from genetic deficiencies in transport proteins and enzymes of the mitochondrial β-oxidation, and milder disease conditions frequently result from conformational destabilization and decreased enzymatic function of the affected proteins. Small molecules which have the ability to raise the functional levels of the affected protein above a certain disease threshold are thus valuable tools for effective drug design. In this work we have investigated the effect of mitochondrial cofactors and metabolites as potential stabilizers in two β-oxidation acyl-CoA dehydrogenases: short chain acyl-CoA dehydrogenase and the medium chain acyl-CoA dehydrogenase as well as glutaryl-CoA dehydrogenase, which is involved in lysine and tryptophan metabolism. We found that near physiological concentrations (low micromolar) of FAD resulted in a spectacular enhancement of the thermal stabilities of these enzymes and prevented enzymatic activity loss during a 1h incubation at 40°C. A clear effect of the respective substrate, which was additive to that of the FAD effect, was also observed for short- and medium-chain acyl-CoA dehydrogenase but not for glutaryl-CoA dehydrogenase. In conclusion, riboflavin may be beneficial during feverish crises in patients with short- and medium-chain acyl-CoA dehydrogenase as well as in glutaryl-CoA dehydrogenase deficiencies, and treatment with substrate analogs to butyryl- and octanoyl-CoAs could theoretically enhance enzyme activity for some enzyme proteins with inherited folding difficulties.► Mitochondrial cofactors and metabolites stabilize SCAD, MCAD and CGD. ► Effect is observed at near physiological concentrations (low micromolar). ► Substrates and FAD have synergistic effect. ► Activity loss is rescued during thermal stress via stability increase. ► Analogs have the potential to theoretically enhance enzyme activity in patients.
Keywords: Abbreviations; ACDH; acyl-CoA dehydrogenases; SCAD; short chain acyl-CoA dehydrogenase; MCAD; medium chain acyl-CoA dehydrogenase; GCD; glutaryl-CoA dehydrogenase; FAD; flavin adenine dinucleotide; DSF; differential scanning fluorimetry; T; m; midpoint of thermal unfoldingFatty acid oxidation; Acyl-CoA dehydrogenase; Chemical chaperone; Differential scanning fluorimetry; Substrate; Thermofluor
Submicromolar Aβ42 reduces hippocampal glutamate receptors and presynaptic markers in an aggregation-dependent manner by Meagan L. Wisniewski; Jeannie Hwang; Ben A. Bahr (pp. 1664-1674).
Synaptic pathology in Alzheimer's disease brains is thought to involve soluble Aβ42 peptide. Here, sterile incubation in PBS caused small Aβ42 oligomer formation as well as heterogeneous, 6E10-immunopositive aggregates of 80–100kDa. The high molecular weight aggregates (H-agg) formed in a time-dependent manner over an extended 30-day period. Interestingly, an inverse relationship between dimeric and H-agg formation was more evident when incubations were performed at 37°C as compared to 23°C, thus providing an experimental strategy with which to address synaptic compromise produced by the different Aβ aggregates. H-agg species formed faster and to higher levels at 37°C compared to 23°C, and the two aggregate preparations were evaluated in hippocampal slice cultures, a sensitive system for monitoring synaptic integrity. Applied daily at 80–600nM for 7days, the Aβ42 preparations caused dose-dependent and aggregation-dependent declines in α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) and N-methyl-d-aspartate (NMDA) receptor subunits as well as in presynaptic components. Unlike the synaptic effects, Aβ42 induced only trace cellular degeneration that was CA1 specific. The 37°C preparation was less effective at decreasing synaptic markers, corresponding with its reduced levels of Aβ42 monomers and dimers. Aβ42 dimers decayed significantly faster at 37°C than 23°C, and more rapidly than monomers at either temperature. These findings indicate that Aβ42 can self-aggregate into potent synaptotoxic oligomers as well as into larger aggregates that may serve to neutralize the toxic formations. These results will add to the growing debate concerning whether high molecular weight Aβ complexes that form amyloid plaques are protective through the sequestration of oligomeric species.► Formation of high molecular weight Aβ42 aggregates is time-dependent. ► High molecular weight aggregates appear to influence Aβ42 dimer decay rate. ► Long term Aβ42 aggregation events lead to reduced synaptotoxicity. ► Sequestering Aβ42 dimers into large aggregates may be protective.
Keywords: Aβ42; Amyloid beta; Alzheimer's disease; GluR1; Aggregation; Synaptic decline
Mechanism of JmjC-containing protein Hairless in the regulation of vitamin D receptor function by Yang Mi; Ye Zhang; Yu-fei Shen (pp. 1675-1680).
The JmjC-domain-containing protein Hairless (HR) and the vitamin D receptor (VDR) play a critical role in the maintenance of hair growth. Mutations in HR or VDR cause alopecia in humans and mice. Here we show that HR interacts with VDR and induces VDR relocalization in the nuclei. HR associates and colocalizes with nuclear receptor co-repressor (N-CoR) which is localized to subnuclear structures termed matrix-associated deacetylase (MAD) bodies. It is found that the HR mutants (C622G, N970S, D1012N, V1136D), associated with alopecia universalis congenita (AUC) or atrichia with papular lesions (APL), exhibit an abnormal subcellular distribution in addition to the impaired co-repressor activity with VDR. Studies on deletion mutants of HR indicate that the JmjC domain contributes to the co-repressor activity of HR. Our work provides new clues and evidence for the understanding on the role of HR in hair growth.► Hairless (HR) induces relocalization of vitamin D receptor (VDR) in the nuclei. ► HR associates and colocalizes with the nuclear receptor corepressor (N-CoR). ► HR mutants exhibit an abnormal subcellular localization and altered nuclear retention.
Keywords: JmjC domain; Nuclear receptor corepressor (N-CoR); Hairless; Vitamin D receptor; Matrix-associated deacetylase (MAD) body
Erratum to “Failure of the feeding response to fasting in carnitine-deficient juvenile visceral steatosis (JVS) mice: Involvement of defective acyl-ghrelin secretion and enhanced corticotropin-releasing factor signaling in the hypothalamus”
by Takeo Sakoguchi; Masahisa Horiuchi; Akihiro Asakawa; Miharu Ushikai; Goichiro Yoshida; Mineko Fujimiya; Ikuo Kato; Masamitsu Nakazato; Toru Takeuchi; Takeyori Saheki; Akio Inui (pp. 1681-1681).