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| Open AccessRETRACTED ARTICLE: TRIB2 confers resistance to anti-cancer therapy by activating the serine/threonine protein kinase AKT
The emergence of drug resistance is a major obstacle in the treatment of cancer patients. Here, the authors show that TRIB2 expression increases resistance to PI3K inhibition by promoting AKT activation and the subsequent FOXO inactivation and disruption of p53 function.
- Richard Hill
- , Patricia A. Madureira
- & Wolfgang Link
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Article
| Open AccessMalignant extracellular vesicles carrying MMP1 mRNA facilitate peritoneal dissemination in ovarian cancer
Ovarian cancer is particularly deadly because it is difficult to detect at the pre-metastatic stage; extracellular vesicles (EVs) on the other hand are involved in the pre-metastatic niche preparation. Here the authors show that EVs mediate ovarian cancer metastasis in the peritoneal area by targeting the mesothelium.
- Akira Yokoi
- , Yusuke Yoshioka
- & Takahiro Ochiya
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| Open AccessIdentification of BPIFA1/SPLUNC1 as an epithelium-derived smooth muscle relaxing factor
Asthma is characterized by abnormal airway hyperresponsiveness. Here the authors identify BPIFA1 as a factor secreted by airway epithelial cells, and show that it regulates contractility of airway smooth muscle cells by binding to and regulating the Orai1 Ca2+channel.
- Tongde Wu
- , Julianne Huang
- & Robert Tarran
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Article
| Open AccessSnf1-related kinase improves cardiac mitochondrial efficiency and decreases mitochondrial uncoupling
The Snf1-related kinase (SNRK) is widely expressed and yet its function is poorly understood. Here the authors show that SNRK regulates mitochondrial coupling via the Trib3-PPARα-UCP3 pathway and that cardiac overexpression of SNRK decreases metabolic substrate usage and oxygen consumption but maintains cardiac function and energy in mice.
- Amy K. Rines
- , Hsiang-Chun Chang
- & Hossein Ardehali
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| Open AccessContractile forces at tricellular contacts modulate epithelial organization and monolayer integrity
EpCAM is an unconventional epithelia-specific cell–cell adhesion molecule, that is mutated in the majority of cases of Congenital Tufting Enteropathy. Here the authors show that loss of EpCAM causes a concentration of contractile activity at tricellular junctions, leading to aberrant apical domain and tight junction displacement.
- Julie Salomon
- , Cécile Gaston
- & Delphine Delacour
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Article
| Open AccessDeath receptor 6 contributes to autoimmunity in lupus-prone mice
Germinal centre (GC) reactions are driven by T follicular helper (Tfh) cells and their dysregulation can cause autoimmune disease. Here the authors show that the orphan receptor DR6 is a Tfh cell marker that binds syndecan-1 on GC B cells driving autoimmunity in lupus-prone mice.
- Daisuke Fujikura
- , Masahiro Ikesue
- & Toshimitsu Uede
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Article
| Open Accessp120-catenin prevents multinucleation through control of MKLP1-dependent RhoA activity during cytokinesis
The tumour suppressor p120-catenin (p120) controls cadherin-based adhesion. Here, the authors demonstrate that p120 regulates cytokinesis through binding to the centralspindlin component MKLP1 and controls RhoA activity. Loss of p120 in cancer induces multinucleation and chromosomal instability, independent of cell-cell adhesion.
- Robert A.H. van de Ven
- , Jolien S. de Groot
- & Patrick W.B. Derksen
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Article
| Open AccessGALNT14 promotes lung-specific breast cancer metastasis by modulating self-renewal and interaction with the lung microenvironment
Polypeptide N-acetyl-galactosaminyltransferases (GALNTs) are associated with cancer, but their function in organ-specific metastasis is unclear. Here the authors show that GALNT14 promotes breast cancer metastasis to the lung by enhancing the initiation of metastatic colonies and subsequent growth.
- Ki-Hoon Song
- , Mi So Park
- & Mi-Young Kim
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Article
| Open AccessOsteoblasts secrete Cxcl9 to regulate angiogenesis in bone
Bone development and vascularization are coupled events that share many molecular mechanisms. Here the authors identify osteoblast-secreted Cxcl9 as an inhibitory regulator of angiogenesis and osteogenesis, and show that mTORC1 signaling and STAT1 are critical upstream mediators of the cytokine expression.
- Bin Huang
- , Wenhao Wang
- & Xiaochun Bai
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Article
| Open AccessPI3 kinase inhibition improves vascular malformations in mouse models of hereditary haemorrhagic telangiectasia
Arteriovenous malformations (AVM) is a hallmark of hereditary haemorrhagic telangiectasia type 2, a disease caused by mutations in BMP receptor ALK1. Ola et al. show that AVM can be caused by blocking BMP9 and BMP10 in mice, leading to increased VEGF and PI3K activity, and that pharmacologic inhibition of PI3K prevents AVM development.
- Roxana Ola
- , Alexandre Dubrac
- & Anne Eichmann
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Article
| Open AccessA mutation in VPS15 (PIK3R4) causes a ciliopathy and affects IFT20 release from the cis-Golgi
VPS15 is known as a VPS34-associated protein that functions in intracellular trafficking and autophagy. Here the authors identify a role for VPS15 in ciliopathy and ciliary phenotypes, and show that it interacts with GM130 and functions in IFT20-dependent cis-Golgi to cilium trafficking.
- Corinne Stoetzel
- , Séverine Bär
- & Hélène Dollfus
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Article
| Open AccessGenome-wide RNAi screen reveals ALK1 mediates LDL uptake and transcytosis in endothelial cells
Atherosclerosis is caused by low-density lipoprotein (LDL) buildup in the vessel wall, a process thought to be mediated by LDL receptor alone. Here, the authors show that the endothelium can uptake LDL via ALK1, a TGFβ signalling receptor, suggesting new therapies for blocking LDL accumulation in the vessel wall.
- Jan R. Kraehling
- , John H. Chidlow
- & William C. Sessa
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Article
| Open AccessGlucose-regulated and drug-perturbed phosphoproteome reveals molecular mechanisms controlling insulin secretion
Dysfunction in insulin secretion is a main driver of type 2 diabetes development. Here the authors monitor phosphoproteome modulation in cells stimulated with glucose and treated with drugs affecting glucose-mediated insulin secretion to reveal phosphorylation sites implicated in insulin secretion control and gene expression regulation.
- Francesca Sacco
- , Sean J. Humphrey
- & Matthias Mann
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Article
| Open AccessOxidative insult can induce malaria-protective trait of sickle and fetal erythrocytes
Carriers of haemoglobinopathies are protected from severe malaria, likely due to reduced surface expression of virulence factors. Here, Cyrklaff et al. show that, similar to haemoglobinopathies, a transient oxidative insult affects actin reorganization and mitigates the development of cerebral malaria in mice.
- Marek Cyrklaff
- , Sirikamol Srismith
- & Michael Lanzer
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Article
| Open Access14-3-3ζ regulates the mitochondrial respiratory reserve linked to platelet phosphatidylserine exposure and procoagulant function
Platelets express negatively charged phosphatidylserine (PS) on their plasma membrane when propagating coagulation within a developing thrombus. Here the authors show that an adaptor protein 14-3-3 regulates mitochondrial function and PS exposure and thus platelet procoagulant activity, promising a new therapy to reduce thrombosis.
- Simone M. Schoenwaelder
- , Roxane Darbousset
- & Shaun P. Jackson
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| Open AccessThe RNA-binding protein vigilin regulates VLDL secretion through modulation of Apob mRNA translation
RNA-binding proteins (RBP) are an emerging group of post-translational regulators. Here the authors show that the RBP vigilin regulates translation of mRNA encoding for proatherogenic proteins—apoB, apoC-III and fibronectin—representing a potential therapeutic target in cardiovascular diseases.
- Mehrpouya B. Mobin
- , Stefanie Gerstberger
- & Markus Stoffel
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Article
| Open AccessFMRP regulates an ethanol-dependent shift in GABABR function and expression with rapid antidepressant properties
Alcohol is thought to lead to neuroadaptive changes, although the underlying molecular mechanisms are unclear. Here, the authors find ethanol treatment alters GABAB-receptor expression via fragile-X mental retardation protein in mice, leading to antidepressant-like behaviours.
- Sarah A. Wolfe
- , Emily R. Workman
- & Kimberly F. Raab-Graham
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| Open AccessGDF11 decreases bone mass by stimulating osteoclastogenesis and inhibiting osteoblast differentiation
GDF11 is related to myostatin yet has no known role in postnatal bone turnover. Here the authors show that recombinant GDF11 injection causes bone loss and impairs healing by driving osteoclastogenesis while inhibiting osteoblast differentiation, plus they show that anti-GDF11 Ab can inhibit bone loss in ovariectomy and ageing mouse models.
- Weiqing Liu
- , Liyan Zhou
- & Quan Yuan
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| Open AccessDysferlin-mediated phosphatidylserine sorting engages macrophages in sarcolemma repair
Sarcolemma lesions are sealed by a repair patch of lipids and proteins that prevents cell death and myopathy. Here the authors show that the "eat-me" signal phosphatidylserine is sorted from adjacent sarcolemma to the repair patch in a Dysferlin dependent process in zebrafish and human cells.
- Volker Middel
- , Lu Zhou
- & Uwe Strähle
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| Open AccessHigh cell-surface density of HER2 deforms cell membranes
HER2 is frequently overexpressed in breast cancer in association with increased metastatic potential. Here, the authors show that HER2 overexpression causes deformation of cell membranes in a signalling-independent manner that contributes to the disease phenotype by disrupting epithelial features.
- Inhee Chung
- , Mike Reichelt
- & Mark X. Sliwkowski
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| Open AccessSuper-resolution microscopy reveals a preformed NEMO lattice structure that is collapsed in incontinentia pigmenti
NEMO is a member of the IKK complex that binds ubiquitin, involved in NF-κB signalling and proposed to form higher order structures. Here the authors use super-resolution microscopy to detect the presence of NEMO lattices in cells, that are modified by NF-κB treatment and abrogated by mutations affecting NEMO ubiquitin binding.
- Janine Scholefield
- , Ricardo Henriques
- & Musa M. Mhlanga
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Article
| Open AccessVCP recruitment to mitochondria causes mitophagy impairment and neurodegeneration in models of Huntington’s disease
Mitochondria defects caused by mutant huntingtin (mtHtt) have been implicated in Huntington's disease. Here authors show that VCP binds to mtHtt on the mitochondria, and that treatment with a peptide that disrupts this interaction reduces the cellular and behavioural deficits in mouse models of HD.
- Xing Guo
- , XiaoYan Sun
- & Xin Qi
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| Open AccessMechanosensing by the α6-integrin confers an invasive fibroblast phenotype and mediates lung fibrosis
Matrix stiffening is a feature of pulmonary fibrosis, and is amplified by lung myofibroblasts. Here the authors find that a6 integrin expression is upregulated on lung myofibroblasts in response to matrix stiffness, and this integrin is required for myofibroblast invasion, and fibrosis in an experimental disease model.
- Huaping Chen
- , Jing Qu
- & Yong Zhou
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Article
| Open AccessPAK proteins and YAP-1 signalling downstream of integrin beta-1 in myofibroblasts promote liver fibrosis
Antifibrotic therapies that target myofibroblast activation are needed to treat chronic liver disease. Here the authors identify an axis of integrin beta-1 expression and Yap-1 and Pak protein signalling that can be interfered with to inhibit myofibroblast function and liver fibrosis in vivo.
- Katherine Martin
- , James Pritchett
- & Karen Piper Hanley
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Editing the genome to introduce a beneficial naturally occurring mutation associated with increased fetal globin
Adult expression of fetal haemoglobin is beneficial and thus desirable in patients with haemoglobin disorders. Here the authors introduce a naturally occurring mutation in the γ-globinpromoter and show that it causes binding of an activator TAL1, chromosome looping and revival of fetal haemoglobin expression in erythroid cells.
- Beeke Wienert
- , Alister P. W. Funnell
- & Merlin Crossley
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ALS-causative mutations in FUS/TLS confer gain and loss of function by altered association with SMN and U1-snRNP
Dominant mutations in the RNA-binding protein FUS/TLS cause amyotrophic lateral sclerosis (ALS), an adult-onset motor neuron degenerative disease. Here, the authors show that ALS-causative FUS/TLS mutations directly bind the SMN and U1-snRNP complexes, producing both loss and gain of function effects on RNA processing.
- Shuying Sun
- , Shuo-Chien Ling
- & Don W. Cleveland
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| Open AccessHuman iPSC-derived motoneurons harbouring TARDBP or C9ORF72 ALS mutations are dysfunctional despite maintaining viability
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects spinal cord motor neurons. Here the authors use induced pluripotent stem cell-derived motor neurons obtained from patients with ALS-linked mutations, and find functional deficits resulting from a progressive decrease in voltage-activated Na+ and K+currents that occur in the absence of cell death.
- Anna-Claire Devlin
- , Karen Burr
- & Gareth B. Miles
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| Open AccessOmega-1 knockdown in Schistosoma mansoni eggs by lentivirus transduction reduces granuloma size in vivo
Schistosomiasis, a neglected tropical disease, is caused by flatworms such as Schistosoma mansoni. Here, Hagen et al. describe a lentivirus-based transduction system to deliver microRNA-adapted small hairpin RNAs into S. mansonito inhibit transcription of selected genes implicated in the disease process.
- Jana Hagen
- , Neil D. Young
- & Bernd H. Kalinna
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| Open AccessPresynaptic GABAergic inhibition regulated by BDNF contributes to neuropathic pain induction
Disinhibition of neural activity in the spinal cord is implicated in neuropathic pain. Chen et al.show that disinhibition of neural activity arises from a shift in reversal potential of GABA and a decrease in the conductance of presynaptic GABA, which are both regulated by brain-derived neurotrophic factor.
- Jeremy Tsung-chieh Chen
- , Da Guo
- & Jing Hu
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Article
| Open AccessDeficient Wnt signalling triggers striatal synaptic degeneration and impaired motor behaviour in adult mice
Synapse degeneration is an early feature of neurodegenerative diseases. Here the authors show that Wnts are endogenous regulators of synaptic maintenance and suggest that dysfunction in Wnt signalling contributes to synaptic degeneration at early stages in neurodegenerative diseases.
- Soledad Galli
- , Douglas M. Lopes
- & Patricia C. Salinas
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Structural analyses of Ca2+/CaM interaction with NaV channel C-termini reveal mechanisms of calcium-dependent regulation
Voltage-gated sodium (NaV) channels initiate action potentials in excitable cells and mutations at NaV loci are responsible for several human diseases. Here, Wang et al. provide novel structural insights into the regulation of NaVchannel activity by calcium-bound calmodulin.
- Chaojian Wang
- , Ben C. Chung
- & Geoffrey S. Pitt
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| Open AccessReversible changes in pancreatic islet structure and function produced by elevated blood glucose
In patients with diabetes, insulin release from pancreatic β-cells is reduced due to altered islet structure and function. Here, Brereton et al. show that elevated blood glucose underlies these changes and is sufficient to reversibly alter β-cell identity in a mouse model of β-cell dysfunction.
- Melissa F. Brereton
- , Michaela Iberl
- & Frances M. Ashcroft
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Helicobacter pylori CagA promotes Snail-mediated epithelial–mesenchymal transition by reducing GSK-3 activity
Gastric cancer is associated with H. pylori infection and these tumours frequently show features of epithelial–mesenchymal transition (EMT). Here, the authors show that the H. pylorivirulence protein, CagA, reduces the activity of GSK3b, which leads to the stabilization of Snail, a protein that induces EMT.
- Da-Gyum Lee
- , Hyun Sil Kim
- & Yong Chan Lee
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Article
| Open AccessGlucose-induced electrical activities and insulin secretion in pancreatic islet β-cells are modulated by CFTR
Patients with cystic fibrosis harbour mutations in the CFTR chloride channel and often develop diabetes for reasons that are poorly understood. Here Guo et al.show that CFTR is involved in the regulation of glucose-stimulated insulin secretion from pancreatic β-cells.
- Jing Hui Guo
- , Hui Chen
- & Hsiao Chang Chan
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The adipokine Retnla modulates cholesterol homeostasis in hyperlipidemic mice
Retnla is an adipokine with known roles in tissue repair and inflammation. Here Lee et al. show that Retnla also promotes cholesterol metabolism and excretion, thereby lowering blood cholesterol levels and reducing the development of atherosclerosis in mice.
- Mi-Ran Lee
- , Chae-ji Lim
- & Goo Taeg Oh
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Plasticity and redundancy among AMA–RON pairs ensure host cell entry of Toxoplasma parasites
Apicomplexan parasites such as Toxoplasma gondii and Plasmodium form a tight, moving junction with host cells before invading them. Here the authors show that the proteins AMA1 and RON2 of T. gondiicooperate during junction formation and identify additional proteins that have a role in this process.
- Mauld H. Lamarque
- , Magali Roques
- & Maryse Lebrun
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S100A11 is required for efficient plasma membrane repair and survival of invasive cancer cells
The cell membrane of metastatic cells is exposed to a variety of physical and chemical stresses. Here, Jaiswal et al. show that S100A11, which is increased in expression in several cancers, is required to promote repair of cell membrane damage in invasive breast cancer cells in vitro.
- Jyoti K. Jaiswal
- , Stine P. Lauritzen
- & Jesper Nylandsted
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An ITAM-Syk-CARD9 signalling axis triggers contact hypersensitivity by stimulating IL-1 production in dendritic cells
Contact hypersensitivity is caused by the reaction of T cells to various chemical contact allergens. Here, the authors unveil the signalling pathway induced in dendritic cells in response to contact allergens, which is required for the stimulation of T-cell sensitization in contact hypersensitivity.
- Shinsuke Yasukawa
- , Yoshiyuki Miyazaki
- & Hiromitsu Hara
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Article
| Open AccessHistamine H3 receptors aggravate cerebral ischaemic injury by histamine-independent mechanisms
Histamine H3 receptor dysregulation is a hallmark of pathological conditions in the central nervous system, and H3 receptor antagonism is neuroprotective. Here Chen et al.show that histamine-independent H3 receptor activation can enhance neuronal cell death during cerebral ischaemia by suppressing autophagy.
- Haijing Yan
- , Xiangnan Zhang
- & Zhong Chen
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Article
| Open AccessIdentification of renin progenitors in the mouse bone marrow that give rise to B-cell leukaemia
Renin cells have traditionally been associated with the kidney where they regulate blood pressure and fluid electrolyte homeostasis. In this study, Belyea et al.describe a renin progenitor in the bone marrow that gives rise to B-cell leukaemia when RBP-J, the final effector of the Notch pathway, is deleted.
- Brian C. Belyea
- , Fang Xu
- & R. Ariel Gomez
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Article
| Open AccessPrelamin A causes progeria through cell-extrinsic mechanisms and prevents cancer invasion
Mutations in the metalloproteinase Zmpste24 preclude prelamin A processing and cause premature ageing. Here, de la Rosaet al.create mosaic Zmpste24 mice, revealing that cell-extrinsic effects are essential for accelerated ageing caused by prelamin A accumulation and that prelamin A reduces invasiveness of cancer cells.
- Jorge de la Rosa
- , José M.P. Freije
- & Carlos López-Otín
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Caspase-2 is required for dendritic spine and behavioural alterations in J20 APP transgenic mice
Aberrant caspase signalling is implicated in Alzheimer’s disease. Pozueta et al.study a mouse model of Alzheimer’s disease that is deficient in caspase-2 and find that surprisingly, these mice don’t display impaired cognitive function, or the reduced dendritic spine density normally associated with the disease.
- Julio Pozueta
- , Roger Lefort
- & Michael Shelanski
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A functional deficiency of TERA/VCP/p97 contributes to impaired DNA repair in multiple polyglutamine diseases
Mutations in polyglutamine proteins are implicated in neurodegenerative disorders. Okazawa and colleagues now demonstrate that mutant polyQ proteins interact directly with the ATPase TERA, resulting in reduced DNA double-strand break repair, which is a feature of neurodegenerative diseases.
- Kyota Fujita
- , Yoko Nakamura
- & Hitoshi Okazawa
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Translation of HTT mRNA with expanded CAG repeats is regulated by the MID1–PP2A protein complex
Expansion of CAG repeats in messenger RNAs is a common feature of various neurodegenerative disorders, including Huntington’s disease. Krauß et al.show that messenger RNAs with expanded CAG repeats bind to a protein complex that regulates translation and promotes overproduction of such aberrant proteins.
- Sybille Krauß
- , Nadine Griesche
- & Susann Schweiger
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A role for calpain-dependent cleavage of TDP-43 in amyotrophic lateral sclerosis pathology
The mislocalization and downregulation of the proteins TDP-43 and ADAR2, respectively, are implicated in amyotrophic lateral sclerosis pathology. Yamashita et al. find that downregulation of ADAR2 results in calcium-permeable AMPA receptor-mediated calpain activation and subsequent aberrant cleavage of TDP-43.
- Takenari Yamashita
- , Takuto Hideyama
- & Shin Kwak
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Alternative splicing of CD44 mRNA by ESRP1 enhances lung colonization of metastatic cancer cell
CD44 is a cell surface protein that is a marker for stem cell-like cancer cells and has a role in invasion and metastasis. Here, epithelial splicing regulatory protein 1 is shown to generate a CD44 variant protein that enhances metastasis in a mouse model and protects cells from oxidative stress.
- Toshifumi Yae
- , Kenji Tsuchihashi
- & Osamu Nagano
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Parkin controls dopamine utilization in human midbrain dopaminergic neurons derived from induced pluripotent stem cells
Mutations in parkin, an ubiquitin ligase, cause an inherited form of Parkinson's disease. Here, Jianget al. generate induced pluripotent stem cells from two patients with parkin mutations and find that neurons derived from the stem cells have defects in dopamine release, dopamine uptake and oxidative metabolism.
- Houbo Jiang
- , Yong Ren
- & Jian Feng
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| Open AccessParkinson's disease induced pluripotent stem cells with triplication of the α-synuclein locus
Pluripotent stem cells can be generated from the somatic cells of humans and are a useful model to study disease. Here, pluripotent stem cells are made from a patient with familial Parkinson's disease, and the resulting neurons exhibit elevated levels of α-synuclein, recapitulating the molecular features of the patient's disease.
- Michael J. Devine
- , Mina Ryten
- & Tilo Kunath
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| Open AccessGenetics and the environment converge to dysregulate N-glycosylation in multiple sclerosis
Complex diseases such as multiple sclerosis have both genetic and environmental components. This study demonstrates that variants of genes implicated in multiple sclerosis, and alterations in cellular metabolism and vitamin D3 levels, alterN-glycosylation, a post-translational modification causal of the disease in mice.
- Haik Mkhikian
- , Ani Grigorian
- & Michael Demetriou