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https://www.readbyqxmd.com/read/28934388/loss-of-slc25a46-causes-neurodegeneration-by-affecting-mitochondrial-dynamics-and-energy-production-in-mice
#1
Zhuo Li, Yanyan Peng, Robert B Hufnagel, Yueh-Chiang Hu, Chuntao Zhao, Luis F Queme, Zaza Khuchua, Ashley M Driver, Fei Dong, Q Richard Lu, Diana M Lindquist, Michael P Jankowski, Rolf W Stottmann, Winston W Y Kao, Taosheng Huang
Recently, we identified biallelic mutations of SLC25A46 in patients with multiple neuropathies. Functional studies revealed that SLC25A46 may play an important role in mitochondrial dynamics by mediating mitochondrial fission. However, the cellular basis and pathogenic mechanism of the SLC25A46-related neuropathies are not fully understood. Thus, we generated a Slc25a46 knock-out mouse model. Mice lacking SLC25A46 displayed severe ataxia, mainly caused by degeneration of Purkinje cells. Increased numbers of small, unmyelinated and degenerated optic nerves as well as loss of retinal ganglion cells indicated optic atrophy...
October 1, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28931858/loss-of-p73-in-ependymal-cells-during-the-perinatal-period-leads-to-aqueductal-stenosis
#2
Masashi Fujitani, Ryohei Sato, Toshihide Yamashita
The p53 family member p73 plays a critical role in brain development. p73 knockout mice exhibit a number of deficits in the nervous system, such as neuronal death, hydrocephalus, hippocampal dysgenesis, and pheromonal defects. Among these phenotypes, the mechanisms of hydrocephalus remain unknown. In this study, we generated a p73 knock-in (KI) mutant mouse and a conditional p73 knockout mouse. The homozygous KI mutants showed aqueductal stenosis. p73 was expressed in the ependymal cell layer and several brain areas...
September 20, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28931820/the-non-canonical-poly-a-polymerase-fam46c-acts-as-an-onco-suppressor-in-multiple-myeloma
#3
Seweryn Mroczek, Justyna Chlebowska, Tomasz M Kuliński, Olga Gewartowska, Jakub Gruchota, Dominik Cysewski, Vladyslava Liudkovska, Ewa Borsuk, Dominika Nowis, Andrzej Dziembowski
FAM46C is one of the most frequently mutated genes in multiple myeloma. Here, using a combination of in vitro and in vivo approaches, we demonstrate that FAM46C encodes an active non-canonical poly(A) polymerase which enhances mRNA stability and gene expression. Reintroduction of active FAM46C into multiple myeloma cell lines, but not its catalytically-inactive mutant, leads to broad polyadenylation and stabilization of mRNAs strongly enriched with those encoding endoplasmic reticulum-targeted proteins and induces cell death...
September 20, 2017: Nature Communications
https://www.readbyqxmd.com/read/28931427/serotonin-5-ht6-receptors-affect-cognition-in-a-mouse-model-of-alzheimer-s-disease-by-regulating-cilia-function
#4
Lili Hu, Bingjie Wang, Yan Zhang
BACKGROUND: Serotonin receptor 5-HT6 is involved in cognition and Alzheimer's disease (AD) development. However, the mechanism of 5-HT6 in AD pathology is not clear. METHODS: Since 5-HT6 is almost exclusively expressed in the primary cilia, using immunostaining we examined the number of cilia in the hippocampus of AD animal model APP/PS1 mice. By overexpressing and knocking down 5-HT6 in the primary cultured hippocampal neurons, we investigated the roles of 5-HT6 in alternating ciliary morphology...
September 20, 2017: Alzheimer's Research & Therapy
https://www.readbyqxmd.com/read/28931410/lentivirus-mediated-interleukin-1%C3%AE-il-1%C3%AE-knock-down-in-the-hippocampus-alleviates-lipopolysaccharide-lps-induced-memory-deficits-and-anxiety-and-depression-like-behaviors-in-mice
#5
Mengmeng Li, Chenli Li, Hanjie Yu, Xiongxiong Cai, Xinbei Shen, Xin Sun, Jinting Wang, Yanhua Zhang, Chuang Wang
BACKGROUND: Recent evidence has suggested that peripheral inflammatory responses induced by lipopolysaccharides (LPS) play an important role in neuropsychiatric dysfunction in rodents. Interleukin-1β (IL-1β), a pro-inflammatory cytokine, has been proposed to be a key mediator in a variety of behavioral dysfunction induced by LPS in mice. Thus, inhibition of IL-1β may have a therapeutic benefit in the treatment of neuropsychiatric disorders. However, the precise underlying mechanism of knock-down of IL-1β in repairing behavioral changes by LPS remains unclear...
September 20, 2017: Journal of Neuroinflammation
https://www.readbyqxmd.com/read/28931049/the-c5a-c5ar1-axis-controls-the-development-of-experimental-allergic-asthma-independent-of-lysm-expressing-pulmonary-immune-cells
#6
Anna V Wiese, Fanny Ender, Katharina M Quell, Konstantina Antoniou, Tillman Vollbrandt, Peter König, Jörg Köhl, Yves Laumonnier
C5a regulates the development of maladaptive immune responses in allergic asthma mainly through the activation of C5a receptor 1 (C5aR1). Yet, the cell types and the mechanisms underlying this regulation are ill-defined. Recently, we described increased C5aR1 expression in lung tissue eosinophils but decreased expression in airway and pulmonary macrophages as well as in pulmonary CD11b+ conventional dendritic cells (cDCs) and monocyte-derived DCs (moDCs) during the allergic effector phase using a floxed green fluorescent protein (GFP)-C5aR1 knock-in mouse...
2017: PloS One
https://www.readbyqxmd.com/read/28930069/initial-elevations-in-glutamate-and-dopamine-neurotransmission-decline-with-age-as-does-exploratory-behavior-in-lrrk2-g2019s-knock-in-mice
#7
Mattia Volta, Dayne A Beccano-Kelly, Sarah A Paschall, Stefano Cataldi, Sarah E MacIsaac, Naila Kuhlmann, Chelsie A Kadgien, Igor Tatarnikov, Jesse Fox, Jaskaran Khinda, Emma Mitchell, Sabrina Bergeron, Heather Melrose, Matthew J Farrer, Austen J Milnerwood
LRRK2 mutations produce end-stage Parkinson's disease (PD) with reduced nigrostriatal dopamine. Conversely, asymptomatic carriers have increased dopamine turnover and altered brain connectivity. LRRK2 pathophysiology remains unclear, but reduced dopamine and mitochondrial abnormalities occur in aged mutant knock-in (GKI) mice. Conversely, cultured GKI neurons exhibit increased synaptic transmission. We assessed behavior and synaptic glutamate and dopamine function across ages. Young GKI exhibit more vertical exploration, elevated glutamate and dopamine transmission, and aberrant D2-receptor responses...
September 20, 2017: ELife
https://www.readbyqxmd.com/read/28929580/selective-expression-of-egfp-in-mouse-perivascular-astrocytes-by-modification-of-the-mlc1-gene-using-t2a-based-ribosome-skipping
#8
Jordan J Toutounchian, Joseph H McCarty
Perivascular astrocyte end feet closely juxtapose cerebral blood vessels to regulate important developmental and physiological processes including endothelial cell proliferation and sprouting as well as the formation of the blood-brain barrier (BBB). The mechanisms underlying these events remain largely unknown due to a lack of experimental models for identifying perivascular astrocytes and distinguishing these cell types from other astroglial populations. Megalencephalic leukoencephalopathy with subcortical cysts 1 (Mlc1) is a transmembrane protein that is expressed in perivascular astrocyte end feet where it controls BBB development and homeostasis...
September 20, 2017: Genesis: the Journal of Genetics and Development
https://www.readbyqxmd.com/read/28928741/cxcl12-mediates-aberrant-costimulation-of-b-lymphocytes-in-warts-hypogammaglobulinemia-infections-myelokathexis-immunodeficiency
#9
Giuliana Roselli, Elisa Martini, Vassilios Lougaris, Raffaele Badolato, Antonella Viola, Marinos Kallikourdis
The Warts, Hypogammaglobulinemia, Infections, Myelokathexis (WHIM) syndrome is an immunodeficiency caused by mutations in chemokine receptor CXCR4. WHIM patient adaptive immunity defects remain largely unexplained. We have previously shown that WHIM-mutant T cells form unstable immunological synapses, affecting T cell activation. Here, we show that, in WHIM patients and WHIM CXCR4 knock-in mice, B cells are more apoptosis prone. Intriguingly, WHIM-mutant B cells were also characterized by spontaneous activation...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28927719/sex-dependent-behavioral-impairments-in-the-hdhq350-mouse-line
#10
Jessica K Cao, Peter J Detloff, Richard G Gardner, Nephi Stella
Huntington's Disease (HD) is an autosomal dominant neurodegenerative disease characterized by gradual deterioration of motor and cognitive functions and development of psychiatric deficits. Animal models provide powerful means to study the pathological processes, molecular dysfunctions and symptoms associated with HD. We performed a longitudinal behavioral study of the newly developed HdhQ350/+ mouse line, a knock-in model that expresses a repeat of 350 glutamines. We found remarkable sex-dependent differences on symptom onset and severity...
September 16, 2017: Behavioural Brain Research
https://www.readbyqxmd.com/read/28926118/chop-induced-loss-of-intestinal-epithelial-stemness-contributes-to-bile-duct-ligation-induced-cholestatic-liver-injury
#11
Runping Liu, Xiaojiaoyang Li, Zhiming Huang, Derrick Zhao, Bhagyalaxmi Sukka Ganesh, Guanhua Lai, William M Pandak, Phillip B Hylemon, Jasmohan S Bajaj, Arun J Sanyal, Huiping Zhou
Impaired intestinal barrier function promotes the progression of various liver diseases including cholestatic liver disease. The close association of primary sclerosing cholangitis (PSC) with inflammatory bowel disease highlights the importance of the gut-liver axis. It has been reported that bile duct ligation (BDL)-induced liver fibrosis is significantly reduced in C/EBP homologous protein knock out (CHOP(-/-) ) mice. However, the underlying mechanisms remain unclear. In the current study, we demonstrate that BDL induces striking and acute hepatic ER stress responses after 1 day, which return to normal after 3 days...
September 19, 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/28923946/immunoreceptor-tyrosine-based-inhibitory-motif-dependent-functions-of-an-mhc-class-i-specific-nk-cell-receptor
#12
Michael D Bern, Diana L Beckman, Takashi Ebihara, Samantha M Taffner, Jennifer Poursine-Laurent, J Michael White, Wayne M Yokoyama
Natural killer (NK) cells express MHC class I (MHC-I)-specific receptors, such as Ly49A, that inhibit killing of cells expressing self-MHC-I. Self-MHC-I also "licenses" NK cells to become responsive to activating stimuli and regulates the surface level of NK-cell inhibitory receptors. However, the mechanisms of action resulting from these interactions of the Ly49s with their MHC-I ligands, particularly in vivo, have been controversial. Definitive studies could be derived from mice with targeted mutations in inhibitory Ly49s, but there are inherent challenges in specifically altering a single gene within a multigene family...
September 18, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28923937/direct-engagement-of-the-pi3k-pathway-by-mutant-kit-dominates-oncogenic-signaling-in-gastrointestinal-stromal-tumor
#13
Benedikt Bosbach, Ferdinand Rossi, Yasemin Yozgat, Jennifer Loo, Jennifer Q Zhang, Georgina Berrozpe, Katherine Warpinski, Imke Ehlers, Darren Veach, Andrew Kwok, Katia Manova, Cristina R Antonescu, Ronald P DeMatteo, Peter Besmer
Gastrointestinal stromal tumors (GISTs) predominantly harbor activating mutations in the receptor tyrosine kinase KIT. To genetically dissect in vivo the requirement of different signal transduction pathways emanating from KIT for tumorigenesis, the oncogenic Kit(V558Δ) mutation was combined with point mutations abrogating specific phosphorylation sites on KIT. Compared with single-mutant Kit(V558Δ/+) mice, double-mutant Kit(V558Δ;Y567F/Y567F) knock-in mice lacking the SRC family kinase-binding site on KIT (pY567) exhibited attenuated MAPK signaling and tumor growth...
September 18, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28923083/prevention-of-c5ar1-signaling-delays-microglial-inflammatory-polarization-favors-clearance-pathways-and-suppresses-cognitive-loss
#14
Michael X Hernandez, Shan Jiang, Tracy A Cole, Shu-Hui Chu, Maria I Fonseca, Melody J Fang, Lindsay A Hohsfield, Maria D Torres, Kim N Green, Rick A Wetsel, Ali Mortazavi, Andrea J Tenner
BACKGROUND: Pharmacologic inhibition of C5aR1, a receptor for the complement activation proinflammatory fragment, C5a, suppressed pathology and cognitive deficits in Alzheimer's disease (AD) mouse models. To validate that the effect of the antagonist was specifically via C5aR1 inhibition, mice lacking C5aR1 were generated and compared in behavior and pathology. In addition, since C5aR1 is primarily expressed on cells of the myeloid lineage, and only to a lesser extent on endothelial cells and neurons in brain, gene expression in microglia isolated from adult brain at multiple ages was compared across all genotypes...
September 18, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28921929/tumor-suppressive-mir-145-co-repressed-by-tcf4-%C3%AE-catenin-and-prc2-complexes-forms-double-negative-regulation-loops-with-its-negative-regulators-in-colorectal-cancer
#15
Wei Wang, Xin Xiao, Xu Chen, Yi Huo, Wen-Jin Xi, Zhi-Feng Lin, Dan Zhang, Yu-Fang Li, Fan Yang, Wei-Hong Wen, An-Gang Yang, Tao Wang
The frequently dysregulated Wnt/β-catenin signaling in different malignancies, by activation of its own or orchestration with other co-factors, regulates various oncogenic or tumor-suppressive genes. Among these genes, miRNAs, which are negative posttranscriptional regulators, are also embedded in the Wnt signaling network. Different from the Wnt-induced oncogenic miRNAs, the specific mechanism underlying the Wnt-repressed tumor-suppressive miRNAs is much less understood. In the present study, firstly by analyzing a ChIP-seq dataset against TCF4, the core transcription factor for initiation of Wnt signaling in colorectal cancer (CRC) cells, we screened out several tumor-suppressive miRNAs potentially regulated by Wnt signaling...
September 16, 2017: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/28920956/biotin-tagging-of-mecp2-in-mice-reveals-contextual-insights-into-the-rett-syndrome-transcriptome
#16
Brian S Johnson, Ying-Tao Zhao, Maria Fasolino, Janine M Lamonica, Yoon Jung Kim, George Georgakilas, Kathleen H Wood, Daniel Bu, Yue Cui, Darren Goffin, Golnaz Vahedi, Tae Hoon Kim, Zhaolan Zhou
Mutations in MECP2 cause Rett syndrome (RTT), an X-linked neurological disorder characterized by regressive loss of neurodevelopmental milestones and acquired psychomotor deficits. However, the cellular heterogeneity of the brain impedes an understanding of how MECP2 mutations contribute to RTT. Here we developed a Cre-inducible method for cell-type-specific biotin tagging of MeCP2 in mice. Combining this approach with an allelic series of knock-in mice carrying frequent RTT-associated mutations (encoding T158M and R106W) enabled the selective profiling of RTT-associated nuclear transcriptomes in excitatory and inhibitory cortical neurons...
September 18, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28919515/trace-amine-associated-receptor-1-regulation-of-methamphetamine-induced-neurotoxicity
#17
Nicholas B Miner, Josh S Elmore, Michael H Baumann, Tamara J Phillips, Aaron Janowsky
Trace amine-associated receptor 1 (TAAR1) is activated by methamphetamine (MA) and modulates dopaminergic (DA) function. Although DA dysregulation is the hallmark of MA-induced neurotoxicity leading to behavioral and cognitive deficits, the intermediary role of TAAR1 has yet to be characterized. To investigate TAAR1 regulation of MA-induced neurotoxicity, Taar1 transgenic knock-out (KO) and wildtype (WT) mice were administered saline or a neurotoxic regimen of 4 i.p. injections, 2hr apart, of MA (2.5, 5, or 10mg/kg)...
September 14, 2017: Neurotoxicology
https://www.readbyqxmd.com/read/28919417/acap3-the-gtpase-activating-protein-specific-to-the-small-gtpase-arf6-regulates-neuronal-migration-in-the-developing-cerebral-cortex
#18
Yuki Miura, Yasunori Kanaho
The GTPase-activating protein (GAP) specific to the small GTPase Arf6, ACAP3, is known to regulate morphogenesis of neurons in vitro. However, physiological significance of ACAP3 in the brain development in vivo remains unclear. Here, we show that ACAP3 is involved in neuronal migration in the developing cerebral cortex of mice. Knockdown of ACAP3 in the developing cortical neurons of mice in utero significantly abrogated neuronal migration in the cortical layer, which was restored by ectopic expression of wild type of ACAP3, but not by its GAP-inactive mutant...
September 15, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28918467/anisodamine-inhibits-endoplasmic-reticulum-stress-associated-txnip-nlrp3-inflammasome-activation-in-rhabdomyolysis-induced-acute-kidney-injury
#19
Xiaopeng Yuan, Yitao Zheng, Chuanbao Chen, Changxi Wang
Anisodamine protects against free radical-induced cellular damage. This study aimed to investigate the protective effect of anisodamine on rhabdomyolysis-induced acute kidney injury (RIAKI). C57BL/6 J mice, TXNIP(-/-) and NLRP3 (-/-) (both were C57BL/6 J background) mice were used to construct RIAKI model. Anisodamine administration was performed on RIAKI mice only. Mice were divided into control, TXNIP-KD (knock down), LNPR3-KD, and anisodamine group (n = 15 in each group). The renal injury, renal function, renal tubular cells apoptosis and expression of Caspase-1, ASC, endoplasmic reticulum (ER) stress markers IRE-1α, CHOP, and ATF4, and interleukin (IL-1α, IL-1β, and IL-18) were detected...
September 16, 2017: Apoptosis: An International Journal on Programmed Cell Death
https://www.readbyqxmd.com/read/28917158/quantitative-trait-locus-mapping-in-mice-identifies-phospholipase-pla2g12a-as-novel-atherosclerosis-modifier
#20
Alexandros Nicolaou, Bernd H Northoff, Kristina Sass, Jana Ernst, Alexander Kohlmaier, Knut Krohn, Christian Wolfrum, Daniel Teupser, Lesca M Holdt
BACKGROUND AND AIMS: In a previous work, a female-specific atherosclerosis risk locus on chromosome (Chr) 3 was identified in an intercross of atherosclerosis-resistant FVB and atherosclerosis-susceptible C57BL/6 (B6) mice on the LDL-receptor deficient (Ldlr(-/-)) background. It was the aim of the current study to identify causative genes at this locus. METHODS: We established a congenic mouse model, where FVB.Chr3(B6/B6) mice carried an 80 Mb interval of distal Chr3 on an otherwise FVB...
September 4, 2017: Atherosclerosis
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