Loss of kallikrein ‐related peptidase 7 exacerbates amyloid pathology in Alzheimer's disease model mice
Abstract
Deposition of amyloid‐β (Aβ) as senile plaques is one of the pathological hallmarks in the brains of Alzheimer's disease (AD) patients. In addition, glial activation has been found in AD brains, although the precise pathological role of astrocytes remains unclear. Here, we identified kallikrein‐related peptidase 7 (KLK7) as an astrocyte‐derived Aβ degrading enzyme. Expression of KLK7 mRNA was significantly decreased in the brains of AD patients. Ablation of Klk7 exacerbated the thioflavin S‐positive Aβ pathology in AD model mice. The expression of Klk7 was upregulated by Aβ treatment in the primary as...
Source: EMBO Molecular Medicine - January 8, 2018 Category: Molecular Biology Authors: Kiwami Kidana, Takuya Tatebe, Kaori Ito, Norikazu Hara, Akiyoshi Kakita, Takashi Saito, Sho Takatori, Yasuyoshi Ouchi, Takeshi Ikeuchi, Mitsuhiro Makino, Takaomi C Saido, Masahiro Akishita, Takeshi Iwatsubo, Yukiko Hori, Taisuke Tomita Tags: Research Article Source Type: research
Loss of RASGRP1 in humans impairs T ‐cell expansion leading to Epstein‐Barr virus susceptibility
Abstract
Inherited CTPS1, CD27, and CD70 deficiencies in humans have revealed key factors of T‐lymphocyte expansion, a critical prerequisite for an efficient immunity to Epstein–Barr virus (EBV) infection. RASGRP1 is a T‐lymphocyte‐specific nucleotide exchange factor known to activate the pathway of MAP kinases (MAPK). A deleterious homozygous mutation in RASGRP1 leading to the loss RASGRP1 expression was identified in two siblings who both developed a persistent EBV infection leading to Hodgkin lymphoma. RASGRP1‐deficient T cells exhibited defective MAPK activation and impaired proliferation that was restored by...
Source: EMBO Molecular Medicine - January 8, 2018 Category: Molecular Biology Authors: Sarah Winter, Emmanuel Martin, David Boutboul, Christelle Lenoir, Sabah Boudjemaa, Arnaud Petit, Capucine Picard, Alain Fischer, Guy Leverger, Sylvain Latour Tags: Research Article Source Type: research
Identification of potential therapeutic targets in prostate cancer through a cross ‐species approach
In this study, we have generated RNAseq data from tumours arising in two established mouse models of prostate cancer, PB‐Cre/PtenloxP/loxP and p53loxP/loxPRbloxP/loxP, and integrated this with published human prostate cancer expression data to pinpoint cancer‐associated gene expression changes that are conserved between the two species. To identify potential therapeutic targets, we then filtered this information for genes that are either known or predicted to be druggable. Using this approach, we revealed a functional role for the kinase MELK as a driver and potential therapeutic target in prostate cancer. We found th...
Source: EMBO Molecular Medicine - January 1, 2018 Category: Molecular Biology Authors: Sarah Jurmeister, Antonio Ramos ‐Montoya, Chiranjeevi Sandi, Nelma Pértega‐Gomes, Karan Wadhwa, Alastair D Lamb, Mark J Dunning, Jan Attig, Jason S Carroll, Lee GD Fryer, Sérgio L Felisbino, David E Neal Tags: Research Article Source Type: research
miR ‐29 contributes to normal endothelial function and can restore it in cardiometabolic disorders
Abstract
We investigated the role of microRNAs (miRNA) in endothelial dysfunction in the setting of cardiometabolic disorders represented by type 2 diabetes mellitus (T2DM). miR‐29 was dysregulated in resistance arterioles obtained by biopsy in T2DM patients. Intraluminal delivery of miR‐29a‐3p or miR‐29b‐3p mimics restored normal endothelium‐dependent vasodilation (EDVD) in T2DM arterioles that otherwise exhibited impaired EDVD. Intraluminal delivery of anti‐miR‐29b‐3p in arterioles from non‐DM human subjects or rats or targeted mutation of Mir29b‐1/a gene in rats led to impaired EDVD and exacerbatio...
Source: EMBO Molecular Medicine - January 1, 2018 Category: Molecular Biology Authors: Michael E Widlansky, David M Jensen, Jingli Wang, Yong Liu, Aron M Geurts, Alison J Kriegel, Pengyuan Liu, Rong Ying, Guangyuan Zhang, Marc Casati, Chen Chu, Mobin Malik, Amberly Branum, Michael J Tanner, Sudhi Tyagi, Kristie Usa, Mingyu Liang Tags: Research Article Source Type: research
Cell –cell signaling in blood vessel development and function
The blood vasculature is an organ pervading all other organs (almost). During vascular development, cell–cell signaling by extracellular ligands and cell surface receptors ensure that new vessels sprout into non‐vascularized regions and simultaneously acquire organ‐specific specializations and adaptations that match the local physiological needs. The vessels thereby specialize in their permeability, molecular transport between blood and tissue, and ability to regulate blood flow on demand. Over the past decades, we have learnt about the generic cell–cell signaling mechanisms governing angiogenic sprouting, mural ce...
Source: EMBO Molecular Medicine - January 1, 2018 Category: Molecular Biology Authors: Christer Betsholtz Tags: Louis ‐Jeantet Prize Winner: Commentary Source Type: research
SEMA3C drives cancer growth by transactivating multiple receptor tyrosine kinases via Plexin B1
Abstract
Growth factor receptor tyrosine kinase (RTK) pathway activation is a key mechanism for mediating cancer growth, survival, and treatment resistance. Cognate ligands play crucial roles in autocrine or paracrine stimulation of these RTK pathways. Here, we show SEMA3C drives activation of multiple RTKs including EGFR, ErbB2, and MET in a cognate ligand‐independent manner via Plexin B1. SEMA3C expression levels increase in castration‐resistant prostate cancer (CRPC), where it functions to promote cancer cell growth and resistance to androgen receptor pathway inhibition. SEMA3C inhibition delays CRPC and enzalutamid...
Source: EMBO Molecular Medicine - January 1, 2018 Category: Molecular Biology Authors: James W Peacock, Ario Takeuchi, Norihiro Hayashi, Liangliang Liu, Kevin J Tam, Nader Al Nakouzi, Nastaran Khazamipour, Tabitha Tombe, Takashi Dejima, Kevin CK Lee, Masaki Shiota, Daksh Thaper, Wilson CW Lee, Daniel HF Hui, Hidetoshi Kuruma, Larissa Ivanov Tags: Research Article Source Type: research
The GPR120 agonist TUG ‐891 promotes metabolic health by stimulating mitochondrial respiration in brown fat
This study demonstrates that the GPR120 agonist TUG‐891 improves metabolic health by activation of brown fat. Mechanistically, TUG‐891 promotes respiration in brown adipocytes by stimulating GPR120‐dependent Ca2+ release and mitochondrial fragmentation, thereby activating UCP1. (Source: EMBO Molecular Medicine)
Source: EMBO Molecular Medicine - January 1, 2018 Category: Molecular Biology Authors: Maaike Schilperoort, Andrea D Dam, Geerte Hoeke, Irina G Shabalina, Anthony Okolo, Aylin C Hanyaloglu, Lea H Dib, Isabel M Mol, Natarin Caengprasath, Yi ‐Wah Chan, Sami Damak, Anne Reifel Miller, Tamer Coskun, Bharat Shimpukade, Trond Ulven, Sander Kooi Tags: Research Article Source Type: research
Inhibition of Drp1/Fis1 interaction slows progression of amyotrophic lateral sclerosis
Abstract
Bioenergetic failure and oxidative stress are common pathological hallmarks of amyotrophic lateral sclerosis (ALS), but whether these could be targeted effectively for novel therapeutic intervention needs to be determined. One of the reported contributors to ALS pathology is mitochondrial dysfunction associated with excessive mitochondrial fission and fragmentation, which is predominantly mediated by Drp1 hyperactivation. Here, we determined whether inhibition of excessive fission by inhibiting Drp1/Fis1 interaction affects disease progression. We observed mitochondrial excessive fragmentation and dysfunction in s...
Source: EMBO Molecular Medicine - January 1, 2018 Category: Molecular Biology Authors: Amit U Joshi, Nay L Saw, Hannes Vogel, Anna D Cunnigham, Mehrdad Shamloo, Daria Mochly ‐Rosen Tags: Research Article Source Type: research
Allele ‐specific silencing therapy for Dynamin 2‐related dominant centronuclear myopathy
Abstract
Rapid advances in allele‐specific silencing by RNA interference established a strategy of choice to cure dominant inherited diseases by targeting mutant alleles. We used this strategy for autosomal‐dominant centronuclear myopathy (CNM), a rare neuromuscular disorder without available treatment due to heterozygous mutations in the DNM2 gene encoding Dynamin 2. Allele‐specific siRNA sequences were developed in order to specifically knock down the human and murine DNM2‐mRNA harbouring the p.R465W mutation without affecting the wild‐type allele. Functional restoration was achieved in muscle from a knock‐in...
Source: EMBO Molecular Medicine - December 15, 2017 Category: Molecular Biology Authors: Delphine Trochet, Bernard Prudhon, Maud Beuvin, C écile Peccate, Stéphanie Lorain, Laura Julien, Sofia Benkhelifa‐Ziyyat, Aymen Rabai, Kamel Mamchaoui, Arnaud Ferry, Jocelyn Laporte, Pascale Guicheney, Stéphane Vassilopoulos, Marc Bitoun Tags: Research Article Source Type: research
Chimeric Pneumoviridae fusion proteins as immunogens to induce cross ‐neutralizing antibody responses
Abstract
Human respiratory syncytial virus (hRSV) and human metapneumovirus (hMPV), two members of the Pneumoviridae family, account for the majority of severe lower respiratory tract infections worldwide in very young children. They are also a frequent cause of morbidity and mortality in the elderly and immunocompromised adults. High levels of neutralizing antibodies, mostly directed against the viral fusion (F) glycoprotein, correlate with protection against either hRSV or hMPV. However, no cross‐neutralization is observed in polyclonal antibody responses raised after virus infection or immunization with purified F pro...
Source: EMBO Molecular Medicine - December 7, 2017 Category: Molecular Biology Authors: Eduardo Olmedillas, Olga Cano, Isidoro Mart ínez, Daniel Luque, María C Terrón, Jason S McLellan, José A Melero, Vicente Más Tags: Research Article Source Type: research
Could blocking the formation of amyloid channels rescue Alzheimer's phenotype?
In a most simplified way, we can say that much of the symptomatology that characterizes Alzheimer's disease (AD) can be attributed to a cascade of toxic events initiated by the presence in the interstitial space of the brain of oligomers of the β‐amyloid peptide (Aβ) peptide, a cleavage by‐product of the Amyloid precursor protein (APP). Intuitively, it follows that the amyloid peptide is the ideal target to combat this disease. However, several anti‐Aβ therapies failed in clinical trials devoted to find a treatment for AD. However, last year, the results of a clinical trial prompted back the interests in this type...
Source: EMBO Molecular Medicine - December 5, 2017 Category: Molecular Biology Authors: Francesc X Guix, Carlos G Dotti Tags: News & Views Source Type: research
Dual IRE1 RNase functions dictate glioblastoma development
This study provides the first demonstration of a dual role of IRE1 downstream signaling in cancer and opens a new therapeutic window to abrogate tumor progression.
The IRE1 arm of the Unfolded Protein Response (UPR) plays a major role in cancer development. Dissecting IRE1 signals in human glioblastoma tumors, primary and established cell lines reveals the dual role of XBP1 mRNA splicing and RIDD in tumor aggressiveness. (Source: EMBO Molecular Medicine)
Source: EMBO Molecular Medicine - December 1, 2017 Category: Molecular Biology Authors: St éphanie Lhomond, Tony Avril, Nicolas Dejeans, Konstantinos Voutetakis, Dimitrios Doultsinos, Mari McMahon, Raphaël Pineau, Joanna Obacz, Olga Papadodima, Florence Jouan, Heloise Bourien, Marianthi Logotheti, Gwénaële Jégou, Néstor Pallares‐Lupo Tags: Research Article Source Type: research
The immunoproteasome ‐specific inhibitor ONX 0914 reverses susceptibility to acute viral myocarditis
Abstract
Severe heart pathology upon virus infection is closely associated with the immunological equipment of the host. Since there is no specific treatment available, current research focuses on identifying new drug targets to positively modulate predisposing immune factors. Utilizing a murine model with high susceptibility to coxsackievirus B3‐induced myocarditis, this study describes ONX 0914—an immunoproteasome‐specific inhibitor—as highly protective during severe heart disease. Represented by reduced heart infiltration of monocytes/macrophages and diminished organ damage, ONX 0914 treatment reversed fulminant...
Source: EMBO Molecular Medicine - December 1, 2017 Category: Molecular Biology Authors: Nadine Althof, Carl Christoph Goetzke, Meike Kespohl, Karolin Voss, Arnd Heuser, Sandra Pinkert, Ziya Kaya, Karin Klingel, Antje Beling Tags: Research Article Source Type: research
Regenerating human epithelia with cultured stem cells: feeder cells, organoids and beyond
Abstract
More than 40 years ago, Howard Green's laboratory developed a method for long‐term expansion of primary human epidermal keratinocytes by co‐culture with 3T3 mouse embryonic fibroblasts. This was a breakthrough for in vitro cultivation of cells from human skin and later for other epithelia: it led to the first stem cell therapy using cultured cells and has vastly increased our understanding of epithelial stem cell biology. In recent years, new methods to expand epithelial cells as three‐dimensional organoids have provided novel means to investigate the functions of these cells in health and disease. Here, w...
Source: EMBO Molecular Medicine - December 1, 2017 Category: Molecular Biology Authors: Robert E Hynds, Paola Bonfanti, Sam M Janes Tags: Review Source Type: research
