Disruption of the astrocytic TNFR1-GDNF axis accelerates motor neuron degeneration and disease progression in amyotrophic lateral sclerosis
In this study, we identified TNF receptor 1 (TNFR1) signalling as a major promoter of GDNF synthesis/release from human and mouse spinal cord astrocytes in vitro and in vivo. To determine whether endogenously produced TNFα can also trigger the synthesis of GDNF in the nervous system, we then focused on SOD1G93A ALS transgenic mice, whose affected tissues spontaneously exhibit high levels of TNFα and its receptor 1 at the onset and symptomatic stage of the disease. In SOD1G93A spinal cords, we verified a strict correlation in the expression of the TNFα, TNFR1 and GDNF triad at different stages of disease p...
Source: Human Molecular Genetics - November 27, 2016 Category: Genetics & Stem Cells Authors: Brambilla, L., Guidotti, G., Martorana, F., Iyer, A. M., Aronica, E., Valori, C. F., Rossi, D. Tags: ARTICLES Source Type: research
AAV-mediated gene therapy in Dystrophin-Dp71 deficient mouse leads to blood-retinal barrier restoration and oedema reabsorption
This study is the basis for the development of new therapeutic strategies in dealing with diseases with BRB breakdown and macular oedema such as diabetic retinopathy (DR). (Source: Human Molecular Genetics)
Source: Human Molecular Genetics - November 27, 2016 Category: Genetics & Stem Cells Authors: Vacca, O., Charles-Messance, H., El Mathari, B., Sene, A., Barbe, P., Fouquet, S., Aragon, J., Darche, M., Giocanti-Auregan, A., Paques, M., Sahel, J.-A., Tadayoni, R., Montanez, C., Dalkara, D., Rendon, A. Tags: ARTICLES Source Type: research
Tead1 regulates the expression of Peripheral Myelin Protein 22 during Schwann cell development
Schwann cells are myelinating glia in the peripheral nervous system that form the myelin sheath. A major cause of peripheral neuropathy is a copy number variant involving the Peripheral Myelin Protein 22 (PMP22) gene, which is located within a 1.4-Mb duplication on chromosome 17 associated with the most common form of Charcot-Marie-Tooth Disease (CMT1A). Rodent models of CMT1A have been used to show that reducing Pmp22 overexpression mitigates several aspects of a CMT1A-related phenotype. Mechanistic studies of Pmp22 regulation identified enhancers regulated by the Sox10 (SRY sex determining region Y-box 10) and Egr2/Krox2...
Source: Human Molecular Genetics - November 27, 2016 Category: Genetics & Stem Cells Authors: Lopez-Anido, C., Poitelon, Y., Gopinath, C., Moran, J. J., Ma, K. H., Law, W. D., Antonellis, A., Feltri, M. L., Svaren, J. Tags: ARTICLES Source Type: research
MeCP2 co-ordinates liver lipid metabolism with the NCoR1/HDAC3 corepressor complex
Rett syndrome (RTT; OMIM 312750), a progressive neurological disorder, is caused by mutations in methyl-CpG-binding protein 2 (MECP2; OMIM 300005), a ubiquitously expressed factor. A genetic suppressor screen designed to identify therapeutic targets surprisingly revealed that downregulation of the cholesterol biosynthesis pathway improves neurological phenotypes in Mecp2 mutant mice. Here, we show that MeCP2 plays a direct role in regulating lipid metabolism. Mecp2 deletion in mice results in a host of severe metabolic defects caused by lipid accumulation, including insulin resistance, fatty liver, perturbed energy utiliza...
Source: Human Molecular Genetics - November 27, 2016 Category: Genetics & Stem Cells Authors: Kyle, S. M., Saha, P. K., Brown, H. M., Chan, L. C., Justice, M. J. Tags: ARTICLES Source Type: research
Cilia gene mutations cause atrioventricular septal defects by multiple mechanisms
In this study we identified deleterious non-synonymous mutations in two cilia genes, Dnah11 and Mks1, in independent N-ethyl-N-nitrosourea-induced mouse mutant lines with heritable recessive AVSDs by whole-exome sequencing. Cilia are required for left/right body axis determination and second heart field (SHF) Hedgehog (Hh) signaling, and we find that cilia mutations affect these requirements differentially. Dnah11avc4 did not disrupt SHF Hh signaling and caused AVSDs only concurrently with heterotaxy, a left/right axis abnormality. In contrast, Mks1avc6 disrupted SHF Hh signaling and caused AVSDs without heterotaxy. We per...
Source: Human Molecular Genetics - November 27, 2016 Category: Genetics & Stem Cells Authors: Burnicka-Turek, O., Steimle, J. D., Huang, W., Felker, L., Kamp, A., Kweon, J., Peterson, M., Reeves, R. H., Maslen, C. L., Gruber, P. J., Yang, X. H., Shendure, J., Moskowitz, I. P. Tags: ARTICLES Source Type: research
Meckels and condylar cartilages anomalies in achondroplasia result in defective development and growth of the mandible
Activating FGFR3 mutations in human result in achondroplasia (ACH), the most frequent form of dwarfism, where cartilages are severely disturbed causing long bones, cranial base and vertebrae defects. Because mandibular development and growth rely on cartilages that guide or directly participate to the ossification process, we investigated the impact of FGFR3 mutations on mandibular shape, size and position. By using CT scan imaging of ACH children and by analyzing Fgfr3Y367C/+ mice, a model of ACH, we show that FGFR3 gain-of-function mutations lead to structural anomalies of primary (Meckel’s) and secondary (condylar...
Source: Human Molecular Genetics - November 27, 2016 Category: Genetics & Stem Cells Authors: Biosse Duplan, M., Komla-Ebri, D., Heuze, Y., Estibals, V., Gaudas, E., Kaci, N., Benoist-Lasselin, C., Zerah, M., Kramer, I., Kneissel, M., Porta, D. G., Di Rocco, F., Legeai-Mallet, L. Tags: ARTICLES Source Type: research
Altered RNA metabolism due to a homozygous RBM7 mutation in a patient with spinal motor neuropathy
We present a patient with SMA-like phenotype carrying a homozygous mutation in RBM7—a subunit of the nuclear exosome targeting (NEXT) complex—which is known to bind and carry specific subtypes of coding and non-coding RNAs to the exosome. The NEXT complex with other protein complexes is responsible for the substrate specificity of the exosome. We performed RNA-sequencing (RNA-seq) analysis on primary fibroblasts of patients with mutations in EXOSC8 and RBM7 and gene knock-down experiments using zebrafish as a model system. RNA-seq analysis identified significantly altered expression of 62 transcripts shared by ...
Source: Human Molecular Genetics - November 27, 2016 Category: Genetics & Stem Cells Authors: Giunta, M., Edvardson, S., Xu, Y., Schuelke, M., Gomez-Duran, A., Boczonadi, V., Elpeleg, O., Müller, J. S., Horvath, R. Tags: ARTICLES Source Type: research
The endoplasmic reticulum-mitochondria interface is perturbed in PARK2 knockout mice and patients with PARK2 mutations
Mutations in PARK2, encoding the E3 ubiquitin protein ligase Parkin, are a common cause of autosomal recessive Parkinson’s disease (PD). Loss of PARK2 function compromises mitochondrial quality by affecting mitochondrial biogenesis, bioenergetics, dynamics, transport and turnover. We investigated the impact of PARK2 dysfunction on the endoplasmic reticulum (ER)-mitochondria interface, which mediates calcium (Ca2+) exchange between the two compartments and is essential for Parkin-dependent mitophagy. Confocal and electron microscopy analyses showed the ER and mitochondria to be in closer proximity in primary fibroblas...
Source: Human Molecular Genetics - November 27, 2016 Category: Genetics & Stem Cells Authors: Gautier, C. A., Erpapazoglou, Z., Mouton-Liger, F., Muriel, M. P., Cormier, F., Bigou, S., Duffaure, S., Girard, M., Foret, B., Iannielli, A., Broccoli, V., Dalle, C., Bohl, D., Michel, P. P., Corvol, J.-C., Brice, A., Corti, O. Tags: ARTICLES Source Type: research
A familial ATP13A2 mutation enhances alpha-synuclein aggregation and promotes cell death
Aberrant protein-protein interactions are a common pathological hallmark among neurodegenerative diseases, including Parkinson’s disease (PD). Thus far, mutations in more than 20 genes have been associated with PD. These genes encode for proteins involved in distinct intracellular pathways, complicating our understanding of the precise molecular mechanisms underlying the disease. Recent reports suggested that the endolysosomal protein ATP13A2 can determine the fate of alpha-synuclein (α-Syn), although no consensus has yet been reached on the mechanisms underlying this effect. Here, we describe, for the first ti...
Source: Human Molecular Genetics - November 27, 2016 Category: Genetics & Stem Cells Authors: Lopes da Fonseca, T., Pinho, R., Outeiro, T. F. Tags: ARTICLES Source Type: research
BIN1 regulates BACE1 intracellular trafficking and amyloid-{beta} production
BIN1 is a genetic risk factor of late-onset Alzheimer disease (AD), which was identified in multiple genome-wide association studies. BIN1 is a member of the amphiphysin family of proteins, and contains N-terminal Bin-Amphiphysin-Rvs and C-terminal Src homology 3 domains. BIN1 is widely expressed in the mouse and human brains, and has been reported to function in the endocytosis and the endosomal sorting of membrane proteins. BACE1 is a type 1 transmembrane aspartyl protease expressed predominantly in neurons of the brain and responsible for the production of amyloid-β peptide (Aβ). Here we report that the deplet...
Source: Human Molecular Genetics - November 27, 2016 Category: Genetics & Stem Cells Authors: Miyagawa, T., Ebinuma, I., Morohashi, Y., Hori, Y., Young Chang, M., Hattori, H., Maehara, T., Yokoshima, S., Fukuyama, T., Tsuji, S., Iwatsubo, T., Prendergast, G. C., Tomita, T. Tags: ARTICLES Source Type: research
Systems-level analysis of human aging genes shed new light on mechanisms of aging
Although studies over the last decades have firmly connected a number of genes and molecular pathways to aging, the aging process as a whole still remains poorly understood. To gain novel insights into the mechanisms underlying aging, instead of considering aging genes individually, we studied their characteristics at the systems level in the context of biological networks. We calculated a comprehensive set of network characteristics for human aging-related genes from the GenAge database. By comparing them with other functional groups of genes, we identified a robust group of aging-specific network characteristics. To find...
Source: Human Molecular Genetics - November 27, 2016 Category: Genetics & Stem Cells Authors: Zhang, Q., Nogales-Cadenas, R., Lin, J.-R., Zhang, W., Cai, Y., Vijg, J., Zhang, Z. D. Tags: ARTICLES Source Type: research
N-acetylcysteine modulates glutamatergic dysfunction and depressive behavior in Huntingtons disease
Glutamatergic dysfunction has been implicated in the pathogenesis of depressive disorders and Huntington’s disease (HD), in which depression is the most common psychiatric symptom. Synaptic glutamate homeostasis is regulated by cystine-dependent glutamate transporters, including GLT-1 and system xc-. In HD, the enzyme regulating cysteine (and subsequently cystine) production, cystathionine--lygase, has recently been shown to be lowered. The aim of the present study was to establish whether cysteine supplementation, using N-acetylcysteine (NAC) could ameliorate glutamate pathology through the cystine-dependent transpo...
Source: Human Molecular Genetics - November 27, 2016 Category: Genetics & Stem Cells Authors: Wright, D. J., Gray, L. J., Finkelstein, D. I., Crouch, P. J., Pow, D., Pang, T. Y., Li, S., Smith, Z. M., Francis, P. S., Renoir, T., Hannan, A. J. Tags: ARTICLES Source Type: research
Targeted inactivation of murine Ddx3x: essential roles of Ddx3x in placentation and embryogenesis
The X-linked DEAD-box RNA helicase DDX3 (DDX3X) is a multifunctional protein that has been implicated in gene regulation, cell cycle control, apoptosis, and tumorigenesis. However, the precise physiological function of Ddx3x during development remains unknown. Here, we show that loss of Ddx3x results in an early post-implantation lethality in male mice. The size of the epiblast marked by Oct3/4 is dramatically reduced in embryonic day 6.5 (E6.5) Ddx3x–/Y embryos. Preferential paternal X chromosome inactivation (XCI) in extraembryonic tissues of Ddx3x heterozygous (Ddx3x–/+) female mice with a maternally inherit...
Source: Human Molecular Genetics - November 27, 2016 Category: Genetics & Stem Cells Authors: Chen, C.-Y., Chan, C.-H., Chen, C.-M., Tsai, Y.-S., Tsai, T.-Y., Wu Lee, Y.-H., You, L.-R. Tags: ARTICLES Source Type: research
RNA-Seq of Huntingtons disease patient myeloid cells reveals innate transcriptional dysregulation associated with proinflammatory pathway activation
Innate immune activation beyond the central nervous system is emerging as a vital component of the pathogenesis of neurodegeneration. Huntington’s disease (HD) is a fatal neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin gene. The systemic innate immune system is thought to act as a modifier of disease progression; however, the molecular mechanisms remain only partially understood. Here we use RNA-sequencing to perform whole transcriptome analysis of primary monocytes from thirty manifest HD patients and thirty-three control subjects, cultured with and without a proinflammatory stimulus. I...
Source: Human Molecular Genetics - November 27, 2016 Category: Genetics & Stem Cells Authors: Miller, J. R. C., Lo, K. K., Andre, R., Hensman Moss, D. J., Träger, U., Stone, T. C., Jones, L., Holmans, P., Plagnol, V., Tabrizi, S. J. Tags: ARTICLES Source Type: research
Table of Contents
(Source: Human Molecular Genetics)
Source: Human Molecular Genetics - November 27, 2016 Category: Genetics & Stem Cells Tags: Cover / Standing Material Source Type: research
