Featured
-
-
Article
| Open AccessPICALM modulates autophagy activity and tau accumulation
The protein PICALM/CALM is implicated in Alzheimer’s disease (AD) pathology, but it is unclear how. In this study, the authors show that CALM regulates clearance of the protein tau, which is also implicated in AD pathology, by facilitating endocytosis-dependent autophagy.
- Kevin Moreau
- , Angeleen Fleming
- & David C. Rubinsztein
-
Article |
Macrophage-inducible C-type lectin underlies obesity-induced adipose tissue fibrosis
The protein Mincle can sense pathogens and molecules associated with cell death. Here the authors show that Mincle expressed in macrophages is a mediator of obesity-induced fibrosis and inflammation of adipose tissue, and that Mincle knockout mice are protected from diet-induced metabolic dysfunction.
- Miyako Tanaka
- , Kenji Ikeda
- & Yoshihiro Ogawa
-
Article |
Genetic deficiency of the mitochondrial protein PGAM5 causes a Parkinson’s-like movement disorder
Mitophagy selectively disposes of dysfunctional mitochondria and defects in this process lead to a variety of mitochondrial diseases. Here the authors report that the mitochondrial protein PGAM5 is required for the stabilization of mitophagy-inducing protein PINK1, and that mice deficient for the gene coding for PGAM5 show signs of neurodegeneration.
- Wei Lu
- , Senthilkumar S. Karuppagounder
- & Michael Lenardo
-
Article |
Full-length TDP-43 forms toxic amyloid oligomers that are present in frontotemporal lobar dementia-TDP patients
TDP-43 proteinopathies are characterized by TDP-43 aggregates but the relationship of these aggregates to the pathogenesis is still not well defined. Here, the authors show that the recombinant full-length human TDP-43 forms oligomers that are neurotoxic, can promote the formation of A-beta amyloid oligomers in vitroand can be detected in postmortem brain of patients.
- Yu-Sheng Fang
- , Kuen-Jer Tsai
- & Yun-Ru Chen
-
Article |
Spatial control of Cdc42 signalling by a GM130–RasGRF complex regulates polarity and tumorigenesis
The small GTPase Cdc42 is an important regulator of cell polarity that localizes to both the plasma membrane and to the Golgi. Baschieri et al.show that the Golgi pool of Cdc42 is regulated by GM130–RasGRF, and that deregulation of this pathway is associated with loss of polarity and tumorigenesis.
- Francesco Baschieri
- , Stefano Confalonieri
- & Hesso Farhan
-
Article |
Loss of Wdfy3 in mice alters cerebral cortical neurogenesis reflecting aspects of the autism pathology
The Wdfy3gene has been associated with autism spectrum disorders in children. Here, the authors examine two separate mutant alleles of this gene in mice and identify its role in cortical neurogenesis, reproducing pathological changes characteristic of the disorder.
- Lori A. Orosco
- , Adam P. Ross
- & Konstantinos S Zarbalis
-
Article |
Megakaryocyte-specific Profilin1-deficiency alters microtubule stability and causes a Wiskott–Aldrich syndrome-like platelet defect
Patients with mutations in the gene encoding the cytoskeleton regulator WAS have platelet defects. Here the authors show that the WAS-binding protein, Profilin1, is essential for platelet formation in mice, and that its deficiency reproduces the bleeding disorder of patients with WAS mutations.
- Markus Bender
- , Simon Stritt
- & Bernhard Nieswandt
-
Article
| Open Accessptk7 mutant zebrafish models of congenital and idiopathic scoliosis implicate dysregulated Wnt signalling in disease
Scoliosis is a complex genetic disorder characterized by spinal curvature. Here, the authors present experimental zebrafish models of idiopathic and congenital scoliosis and suggest a role for dysregulated Wnt activity in scoliosis aetiology.
- Madeline Hayes
- , Xiaochong Gao
- & Brian Ciruna
-
Article |
Microbial genomic analysis reveals the essential role of inflammation in bacteria-induced colorectal cancer
Abundance of certain gut enterobacteria is correlated with inflammation and cancer development in humans, but the interplay between the three factors is unclear. Here the authors show that gut inflammation is required for bacteria-associated tumour development in mouse models.
- Janelle C. Arthur
- , Raad Z. Gharaibeh
- & Christian Jobin
-
Article |
Loss of PIKfyve in platelets causes a lysosomal disease leading to inflammation and thrombosis in mice
PIKfyve is a lipid kinase essential for regulation of membrane homeostasis and vesicle trafficking along the endosomal-lysosomal pathway. Here the authors show that mice lacking PIKfyve exclusively in their platelets exhibit a systemic disorder characterized by multi-organ inflammation and thrombosis due to aberrant platelet lysosome function.
- Sang H. Min
- , Aae Suzuki
- & Charles S. Abrams
-
Article |
Glucocerebrosidase depletion enhances cell-to-cell transmission of α-synuclein
Transmission of alpha-synuclein aggregates between neurons has been observed in animal models of Parkinson’s disease, however, the mechanism of transmission remains unclear. Bae et al. report that a cycle of uptake, co-aggregation and exocytosis is enhanced by loss of glucocerebrosidase activity.
- Eun-Jin Bae
- , Na-Young Yang
- & Seung-Jae Lee
-
Article |
High susceptibility to fatty liver disease in two-pore channel 2-deficient mice
Two-pore channel 2 has been implicated in coupling changes in cellular energy status with endolysosomal function. Grimm et al.show that mice lacking this channel display defects in endolysosomal trafficking of LDL-cholesterol and are susceptible to hepatic cholesterol overload and fatty liver disease.
- Christian Grimm
- , Lesca M. Holdt
- & Christian Wahl-Schott
-
Article |
Genome-wide association study identifies new susceptibility loci for epithelial ovarian cancer in Han Chinese women
Ovarian cancer is common among women and is the leading cause of death from gynaecological malignancies. Here the authors identify two previously unknown genetic variants that increase the risk of epithelial ovarian cancer in Han Chinese women.
- Kexin Chen
- , Hongxia Ma
- & Qingyi Wei
-
Article |
Innate immunodeficiency following genetic ablation of Mcl1 in natural killer cells
Mcl-1 is an important survival factor for several hematopoietic lineages including B and T lymphocytes, but its role in the Natural Killer (NK) cells has not been previously tested. Here, the authors report that deletion of Mcl-1 in the NK cell lineage leads to the loss of NK cells from all tissues.
- Priyanka Sathe
- , Rebecca B. Delconte
- & Nicholas D. Huntington
-
Article |
Telomerase stimulates ribosomal DNA transcription under hyperproliferative conditions
Several recent studies suggest that telomerase has key physiologic functions beyond its well-known role telomere maintenance. Here, Garcia Gonzalez et al. implicate telomerase in the regulation of ribosomal DNA transcription by RNA polymerase I.
- Omar Garcia Gonzalez
- , Robin Assfalg
- & Sebastian Iben
-
Article |
Frequent cases of RAS-mutated Down syndrome acute lymphoblastic leukaemia lack JAK2 mutations
For children with acute lymphoblastic leukaemia (ALL), those with Down syndrome (DS) have decreased survival compared with children without DS. Here, the authors use exome sequencing to characterise the mutational landscape of patients with both ALL and DS and highlight genes related to survival and relapse.
- Sergey I. Nikolaev
- , Marco Garieri
- & Stylianos E. Antonarakis
-
Article |
Early-onset metabolic syndrome in mice lacking the intestinal uric acid transporter SLC2A9
Elevated blood levels of urate have been linked to metabolic diseases. Here the authors show that the urate transporter, GLUT9, in enterocytes is important for the extrarenal excretion of urate, and that primary hyperuricaemia in mice lacking Glut9 is sufficient to develop metabolic syndrome.
- Brian J DeBosch
- , Oliver Kluth
- & Kelle Moley
-
Article |
Nitric oxide enhances Th9 cell differentiation and airway inflammation
Th9 cells are a subset of T helper cells that protect hosts against helminthic infection, but can also mediate allergic disease through overexpression of the cytokine IL-9. Here, Niedbala et al.show that nitric oxide is a potent enhancer of Th9 differentiation via the activation of p53 protein.
- Wanda Niedbala
- , Anne-Gaelle Besnard
- & Foo Y. Liew
-
Article
| Open AccessAlarmin S100A8/S100A9 as a biomarker for molecular imaging of local inflammatory activity
Alarmins are locally released during inflammation and are early amplifiers of inflammation. Here Vogl et al.show that the alarmin S100A8/S100A9 can be used as a sensitive marker to detect subclinical inflammation and follow disease progression in a variety of disease models.
- Thomas Vogl
- , Michel Eisenblätter
- & Johannes Roth
-
Article
| Open AccessHGK/MAP4K4 deficiency induces TRAF2 stabilization and Th17 differentiation leading to insulin resistance
HGK kinase is involved in signalling in many cell types but its function in T cells remains unclear. Here, using T-cell-specific HGK knockout mice, the authors show that HGK prevents the development of systemic inflammation and insulin resistance by inhibiting production of the proinflammatory cytokines IL-6 and IL-17.
- Huai-Chia Chuang
- , Wayne H. -H. Sheu
- & Tse-Hua Tan
-
Article |
BCLAF1 and its splicing regulator SRSF10 regulate the tumorigenic potential of colon cancer cells
Alternative splicing often alters the biological function of proteins. Here, Zhou et al. show that the splicing factor SRSF10 directs the inclusion of exon5a in Bcl-2-associated transcription factor 1, and that this drives cell growth and tumorigenic potential in human colon cancer cells.
- Xuexia Zhou
- , Xuebing Li
- & Ying Feng
-
Article |
SOX2 is a cancer-specific regulator of tumour initiating potential in cutaneous squamous cell carcinoma
The mechanisms that sustain the self-renewal and expansion of cancer cells with tumour initiating potential are not completely understood. Here the authors show that the transcription factor, Sox2, marks tumour initiating cells in cutaneous squamous cell carcinomas and is required for their expansion.
- Jasmin M. Siegle
- , Alice Basin
- & Markus Schober
-
Article |
GIV/Girdin is a central hub for profibrogenic signalling networks during liver fibrosis
Liver fibrosis involves the activation of hepatic stellate cells (HSCs). Here the authors show that the guanine exchange factor GIV is specifically upregulated in HSCs, and that it serves as an integrator of multi-receptor driven pro-fibrotic signalling in the liver via its ability to activate G proteins.
- Inmaculada Lopez-Sanchez
- , Ying Dunkel
- & Pradipta Ghosh
-
Article
| Open AccessRole of astroglia in Down’s syndrome revealed by patient-derived human-induced pluripotent stem cells
Down’s syndrome is characterized by intellectual disability and other neuropathological symptoms. Here, the authors show that astroglia derived from induced pluripotent stem cells from Down’s syndrome patients impair the development of neurons, and that this can be attenuated with the drug minocycline.
- Chen Chen
- , Peng Jiang
- & Wenbin Deng
-
Article |
Src-dependent impairment of autophagy by oxidative stress in a mouse model of Duchenne muscular dystrophy
Defective autophagy is associated with the pathogenesis of Duchenne muscular dystrophy (DMD). Pal et al. reveal that activation of Src kinase by oxidative stress is responsible for impairment of autophagy in the muscles of mdxmice, and show that reducing oxidative stress rescues autophagy in this DMD model.
- Rituraj Pal
- , Michela Palmieri
- & George G. Rodney
-
Article |
PKM2 regulates the Warburg effect and promotes HMGB1 release in sepsis
The role of metabolic reprogramming in the regulation of innate inflammatory response remains incompletely understood. Here, the authors show that pyruvate kinase M2-mediated aerobic glycolysis contributes to inflammatory response, and that inhibition of this pathway protects mice from lethal endotoxemia and sepsis.
- Liangchun Yang
- , Min Xie
- & Daolin Tang
-
Article |
An ALS-associated mutation in the FUS 3′-UTR disrupts a microRNA–FUS regulatory circuitry
Abnormal accumulation of the RNA-binding protein FUS and mutations within the FUS gene have been found in association with amyotrophic lateral sclerosis (ALS). Here, Dini Modigliani et al.uncover a FUS regulatory circuit that implicates the microRNAs miR-141 and miR-200a in a feedback loop disrupted by an ALS-associated mutation.
- Stefano Dini Modigliani
- , Mariangela Morlando
- & Irene Bozzoni
-
Article
| Open AccessPrion neuropathology follows the accumulation of alternate prion protein isoforms after infective titre has peaked
Prions (PrP) are infectious agents that cause lethal neurodegenerative diseases. Here the authors study the kinetics of prion propagation in mice and show that the onset of neuropathology occurs during the late phase of disease and is hypothesized to be due to increases in a toxic isoform of PrP that is different from the infectious species.
- Malin K. Sandberg
- , Huda Al-Doujaily
- & John Collinge
-
Article |
Modelling Fanconi anemia pathogenesis and therapeutics using integration-free patient-derived iPSCs
Fanconi anaemia (FA) is a genetic disease associated with low levels of blood stem cells. Here Liu et al.report an improved method to generate genetically corrected induced pluripotent stem cells from an FA patient, and perform a screening to identify drugs that improve their differentiation into blood stem cells.
- Guang-Hui Liu
- , Keiichiro Suzuki
- & Juan Carlos Izpisua Belmonte
-
Article |
Ezh2 loss promotes development of myelodysplastic syndrome but attenuates its predisposition to leukaemic transformation
Mutations in the EZH2 gene are found in myelodysplastic syndrome (MDS) and are often accompanied by mutations in RUNX1. Here, the authors develop a mouse model of MDS and show that EZH2loss enhances the RUNX1-mediated MDS pathology.
- Goro Sashida
- , Hironori Harada
- & Atsushi Iwama
-
Article
| Open AccessThe impact of the metabotropic glutamate receptor and other gene family interaction networks on autism
The autism spectrum disorders are complex genetic traits characterized by various neurodevelopmental deficits. Here, the authors analyse defective gene family interaction networks in autism cases and healthy controls and identify potential gene family interactions that may contribute to autism aetiology.
- Dexter Hadley
- , Zhi-liang Wu
- & Hakon Hakonarson
-
Article |
Tonic inhibition in dentate gyrus impairs long-term potentiation and memory in an Alzheimer’s disease model
Altered GABAergic synaptic transmission is implicated in Alzheimer’s disease pathology. Here, Wu et al. show that GABA content is increased in brain samples from human patients and that in mouse models of the disease, the increase in GABA leads to an increase in tonic inhibition in the dentate gyrus.
- Zheng Wu
- , Ziyuan Guo
- & Gong Chen
-
Article |
iPSC-derived neurons from GBA1-associated Parkinson’s disease patients show autophagic defects and impaired calcium homeostasis
Mutations in the gene, GBA1, cause Gaucher’s disease, and are a strong risk factor for the development of Parkinson’s disease. Here the authors use cells derived from Parkinson’s patients with GBA1mutations to model the disease, and reveal changes in cellular recycling systems that may promote neurodegeneration.
- David C. Schöndorf
- , Massimo Aureli
- & Michela Deleidi
-
Article
| Open AccessHomeostatic control of polo-like kinase-1 engenders non-genetic heterogeneity in G2 checkpoint fidelity and timing
Cells exposed to DNA damage delay mitotic entry to allow repair. Liang et al. unexpectedly find that the duration of arrest and the completeness of repair vary from cell to cell, determined by progressively increasing polo-like kinase-1 activity, which must pass a threshold to trigger mitosis.
- Hongqing Liang
- , Alessandro Esposito
- & Ashok R. Venkitaraman
-
Article
| Open AccessPathological α-synuclein impairs adult-born granule cell development and functional integration in the olfactory bulb
Aggregation-prone forms of α-synuclein lead to degeneration of midbrain dopaminergic neurons, as seen in Parkinson’s disease, but less is known about the effects that the noxious protein has in other brain regions. Here, the authors investigate the effect of a pathological form of α-synuclein on the functional integration of new neurons into the olfactory bulb of adult mice.
- Johanna Neuner
- , Saak V. Ovsepian
- & Jochen Herms
-
Article
| Open AccessConformational targeting of intracellular Aβ oligomers demonstrates their pathological oligomerization inside the endoplasmic reticulum
Intracellular Aß oligomers have been linked to Alzheimer’s disease but details about their biosynthesis and function have been hard to obtain due to the lack of selective approaches for targeting them. Here, Meli et al.develop a strategy using recombinant antibodies to target Aß oligomers in the endoplasmic reticulum of cells, and perform mechanistic studies in cellular models of the disease.
- Giovanni Meli
- , Agnese Lecci
- & Antonino Cattaneo
-
Article |
Association analysis identifies new risk loci for non-obstructive azoospermia in Chinese men
Non-obstructive azoospermia (NOA) is a major cause of male infertility. Here, the authors provide insight into the genetic basis of NOA by identifying three new genetic risk loci in a genome-wide association study and reporting a fourth potential NOA susceptibility locus based on a Drosophilaknockdown experiment.
- Zhibin Hu
- , Zheng Li
- & Jiahao Sha
-
Article
| Open AccessPathogenic potential of interferon αβ in acute influenza infection
Interferon αβ(IFNαβ) is known as a potent anti-viral factor, yet its role in influenza infection remains controversial. Here, the authors show that the IFNαβ response is a critical host factor, which, when excessive, causes strong inflammation and severe disease in a mouse model of acute influenza infection.
- Sophia Davidson
- , Stefania Crotta
- & Andreas Wack
-
Article |
Contribution of the R-Ras2 GTP-binding protein to primary breast tumorigenesis and late-stage metastatic disease
Ras family members have critical roles in many types of tumours but the role of R-Ras2 in cancer is unclear. Here the authors show that R-Ras2 is important in both the formation of breast primary tumours and metastasis to the lung.
- Romain M. Larive
- , Giulia Moriggi
- & Xosé R. Bustelo
-
Article |
The covalent modifier Nedd8 is critical for the activation of Smurf1 ubiquitin ligase in tumorigenesis
E3 ligases that attach ubiquitin to proteins destined for proteasomal degradation are regulated by neddylation. In this study, Xie et al. show that the HECT ligase Smurf1, which is a ubiquitin ligase, is also neddylated, and this post-translational modification enhances its ligase activity.
- Ping Xie
- , Minghua Zhang
- & Lingqiang Zhang
-
Article
| Open AccessMutation in VPS35 associated with Parkinson’s disease impairs WASH complex association and inhibits autophagy
Parkinson’s disease can be caused by a rare mutation in the protein VPS35, but the mechanism responsible for this is largely unknown. Here, Zavodszky et al.show that this mutation leads to defects in the recruitment of endosomal protein sorting machinery and consequent inhibition of autophagy in cells.
- Eszter Zavodszky
- , Matthew N.J. Seaman
- & David C. Rubinsztein
-
Article
| Open AccessTranscription factor IRF5 drives P2X4R+-reactive microglia gating neuropathic pain
In response to neuronal injury or disease, microglia adopt distinct reactive phenotypes via the expression of proteins, such as the purinergic P2X4 receptor. Here, Masuda et al.show that the transcription factor axis, interferon regulatory factor-8 and -5, drives the expression of P2X4 receptor in microglia and the adoption of a reactive phenotype after peripheral nerve injury.
- Takahiro Masuda
- , Shosuke Iwamoto
- & Kazuhide Inoue
-
Article |
Oncogenic Ras induces inflammatory cytokine production by upregulating the squamous cell carcinoma antigens SerpinB3/B4
The Ras oncogene has many different roles in cancer including the production of cytokines that can influence the tumour microenvironment. Here, Catanzaro et al.demonstrate that Ras can modulate the expression of SerpinB3/B4, which leads to increased cytokine production and tumour growth.
- Joseph M. Catanzaro
- , Namratha Sheshadri
- & Wei-Xing Zong
-
Article |
Bhlhe40 controls cytokine production by T cells and is essential for pathogenicity in autoimmune neuroinflammation
T cells that mediate neuroinflammation in EAE, a mouse model of multiple sclerosis, act through their production of cytokines. Here, the authors show that the transcription factor Bhlhe40 regulates the expression of GM-CSF and IL-10 by autoreactive T cells and is crucial for EAE induction.
- Chih-Chung Lin
- , Tara R. Bradstreet
- & Brian T. Edelson
-
Article
| Open AccessSLC7A14 linked to autosomal recessive retinitis pigmentosa
Retinitis pigmentosa is the leading cause of inherited blindness worldwide. Here, the authors use exome sequencing to identify mutations in SLC7A14that may be linked to the disease, and provide functional support for the role of this gene in retinal development and visual function in mice and zebrafish.
- Zi-Bing Jin
- , Xiu-Feng Huang
- & Jia Qu
-
Article |
Disrupting MLC1 and GlialCAM and ClC-2 interactions in leukodystrophy entails glial chloride channel dysfunction
Defects in the cell adhesion molecule GlialCAM, the membrane protein MLC1 and the chloride channel ClC-2 are implicated in leukodystrophy. Here, Hoegg-Beiler et al.show that these proteins form a functional complex to maintain homoeostatic chloride ion transport supporting normal glial function in mice.
- Maja B. Hoegg-Beiler
- , Sònia Sirisi
- & Thomas J. Jentsch
-
Article
| Open AccessBlockade of TLR3 protects mice from lethal radiation-induced gastrointestinal syndrome
Ionizing radiation damages small intestinal crypt cells, including epithelial stem cells and their progeny. Here the authors show that radiation-induced crypt cell death is amplified by the release of cellular RNA from apoptotic epithelial cells, which then triggers pro-apoptotic TLR3 signalling on neighbouring cells.
- Naoki Takemura
- , Takumi Kawasaki
- & Satoshi Uematsu
-
Article |
Genome-wide association study reveals two new risk loci for bipolar disorder
Bipolar disorder (BD) is a severe mood disorder, which has been shown to have a large genetic component. Here the authors identify two previously unreported BD risk loci and provide further insights into the biological mechanisms underlying BD development.
- Thomas W. Mühleisen
- , Markus Leber
- & Sven Cichon
-
Article |
Decreased CALM expression reduces Aβ42 to total Aβ ratio through clathrin-mediated endocytosis of γ-secretase
CALM is an adaptor protein required for clathrin-mediated endocytosis, and is a protective factor in Alzheimer’s disease. Here, Kanatsu et al.show that CALM can reduce the production of toxic Aß42 protein by driving clathrin-mediated endocytosis of γ-secretase.
- Kunihiko Kanatsu
- , Yuichi Morohashi
- & Takeshi Iwatsubo