Multiple Domain Interfaces Mediate SARM1 Autoinhibition
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PARSANA-DISSERTATION-2020.Pdf
DECIPHERING TRANSCRIPTIONAL PATTERNS OF GENE REGULATION: A COMPUTATIONAL APPROACH by Princy Parsana A dissertation submitted to The Johns Hopkins University in conformity with the requirements for the degree of Doctor of Philosophy Baltimore, Maryland July, 2020 © 2020 Princy Parsana All rights reserved Abstract With rapid advancements in sequencing technology, we now have the ability to sequence the entire human genome, and to quantify expression of tens of thousands of genes from hundreds of individuals. This provides an extraordinary opportunity to learn phenotype relevant genomic patterns that can improve our understanding of molecular and cellular processes underlying a trait. The high dimensional nature of genomic data presents a range of computational and statistical challenges. This dissertation presents a compilation of projects that were driven by the motivation to efficiently capture gene regulatory patterns in the human transcriptome, while addressing statistical and computational challenges that accompany this data. We attempt to address two major difficulties in this domain: a) artifacts and noise in transcriptomic data, andb) limited statistical power. First, we present our work on investigating the effect of artifactual variation in gene expression data and its impact on trans-eQTL discovery. Here we performed an in-depth analysis of diverse pre-recorded covariates and latent confounders to understand their contribution to heterogeneity in gene expression measurements. Next, we discovered 673 trans-eQTLs across 16 human tissues using v6 data from the Genotype Tissue Expression (GTEx) project. Finally, we characterized two trait-associated trans-eQTLs; one in Skeletal Muscle and another in Thyroid. Second, we present a principal component based residualization method to correct gene expression measurements prior to reconstruction of co-expression networks. -
Palmitoylation Enables MAPK-Dependent Proteostasis of Axon Survival Factors
Palmitoylation enables MAPK-dependent proteostasis of axon survival factors Daniel W. Summersa,b, Jeffrey Milbrandtb,c,1, and Aaron DiAntonioa,c,1 aDepartment of Developmental Biology, Washington University in St. Louis School of Medicine, St. Louis, MO 63110; bDepartment of Genetics, Washington University in St. Louis School of Medicine, St. Louis, MO 63110; and cHope Center for Neurological Disorders, Washington University in St. Louis School of Medicine, St. Louis, MO 63110 Edited by Yishi Jin, University of California, San Diego, La Jolla, CA, and accepted by Editorial Board Member Yuh Nung Jan July 31, 2018 (received for review April 22, 2018) Axon degeneration is a prominent event in many neurodegener- than NMNAT2 (15). Both NMNAT2 and SCG10 are short-lived ative disorders. Axon injury stimulates an intrinsic self-destruction proteins, and constant delivery to the axon is necessary for axon program that culminates in activation of the prodegeneration survival (15, 16). In addition, NMNAT2 and SCG10 are palmi- factor SARM1 and local dismantling of damaged axon segments. In toylated and associated with vesicles that are anterogradely healthy axons, SARM1 activity is restrained by constant delivery of transported through the axon (17–19). Surprisingly, membrane the axon survival factor NMNAT2. Elevating NMNAT2 is neuro- association promotes NMNAT2 degradation in HEK293t cells protective, while loss of NMNAT2 evokes SARM1-dependent axon (20), yet whether this occurs in axons is unknown. Inhibiting degeneration. As a gatekeeper of axon survival, NMNAT2 abundance pathways responsible for NMNAT2 degradation is neuro- is an important regulatory node in neuronal health, highlighting the protective, reinforcing the need to understand molecular mech- need to understand the mechanisms behind NMNAT2 protein ho- anisms of NMNAT2 protein homeostasis in the axon. -
Nicotinamide Adenine Dinucleotide Is Transported Into Mammalian
RESEARCH ARTICLE Nicotinamide adenine dinucleotide is transported into mammalian mitochondria Antonio Davila1,2†, Ling Liu3†, Karthikeyani Chellappa1, Philip Redpath4, Eiko Nakamaru-Ogiso5, Lauren M Paolella1, Zhigang Zhang6, Marie E Migaud4,7, Joshua D Rabinowitz3, Joseph A Baur1* 1Department of Physiology, Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States; 2PARC, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States; 3Lewis-Sigler Institute for Integrative Genomics, Department of Chemistry, Princeton University, Princeton, United States; 4School of Pharmacy, Queen’s University Belfast, Belfast, United Kingdom; 5Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States; 6College of Veterinary Medicine, Northeast Agricultural University, Harbin, China; 7Mitchell Cancer Institute, University of South Alabama, Mobile, United States Abstract Mitochondrial NAD levels influence fuel selection, circadian rhythms, and cell survival under stress. It has alternately been argued that NAD in mammalian mitochondria arises from import of cytosolic nicotinamide (NAM), nicotinamide mononucleotide (NMN), or NAD itself. We provide evidence that murine and human mitochondria take up intact NAD. Isolated mitochondria preparations cannot make NAD from NAM, and while NAD is synthesized from NMN, it does not localize to the mitochondrial matrix or effectively support oxidative phosphorylation. Treating cells *For correspondence: with nicotinamide riboside that is isotopically labeled on the nicotinamide and ribose moieties [email protected] results in the appearance of doubly labeled NAD within mitochondria. Analogous experiments with †These authors contributed doubly labeled nicotinic acid riboside (labeling cytosolic NAD without labeling NMN) demonstrate equally to this work that NAD(H) is the imported species. -
Sciencedirect.Com
Available online at www.sciencedirect.com ScienceDirect Axon degeneration: context defines distinct pathways 1,2 1,2 Matthew J Geden and Mohanish Deshmukh Axon degeneration is an essential part of development, In the mammalian model, mechanistic details of axon plasticity, and injury response and has been primarily studied in degeneration has been predominantly studied in vitro in mammalian models in three contexts: 1) Axotomy-induced three contexts: 1) Axotomy (also known as Wallerian Wallerian degeneration, 2) Apoptosis-induced axon degeneration), where the severing of axons results in degeneration (axon apoptosis), and 3) Axon pruning. These the degeneration of axons distal to the cut site; 2) Apo- three contexts dictate engagement of distinct pathways for ptosis-induced Axon Degeneration, which we define here axon degeneration. Recent advances have identified the as ‘Axon Apoptosis’, where the entire neuron is exposed importance of SARM1, NMNATs, NAD+ depletion, and MAPK to apoptotic stimuli (e.g. global deprivation of trophic signaling in axotomy-induced Wallerian degeneration. factors) resulting in the degeneration of both axons and Interestingly, apoptosis-induced axon degeneration and axon soma; and 3) Pruning-induced Axon Degeneration, which pruning have many shared mechanisms both in signaling (e.g. we refer to here as ‘Axon Pruning’, where a subset of DLK, JNKs, GSK3a/b) and execution (e.g. Puma, Bax, axons are selectively exposed to a pruning stimuli (e.g. caspase-9, caspase-3). However, the specific mechanisms by axon-only or ‘local’ deprivation of trophic factors) which which caspases are activated during apoptosis versus pruning results in the selective degeneration of only the axons appear distinct, with apoptosis requiring Apaf-1 but not exposed to the stimulus. -
Identification of Evolutionary and Kinetic Drivers of NAD-Dependent Signaling
Identification of evolutionary and kinetic drivers of NAD-dependent signaling Mathias Bockwoldta, Dorothée Houryb, Marc Nierec, Toni I. Gossmannd,e, Ines Reinartzf,g, Alexander Schugh, Mathias Zieglerc, and Ines Heilanda,1 aDepartment of Arctic and Marine Biology, UiT The Arctic University of Norway, 9017 Tromsø, Norway; bDepartment of Biological Sciences, University of Bergen, 5006 Bergen, Norway; cDepartment of Biomedicine, University of Bergen, 5009 Bergen, Norway; dDepartment of Animal and Plant Sciences, Western Bank, University of Sheffield, S10 2TN Sheffield, United Kingdom; eDepartment of Animal Behaviour, Bielefeld University, 33501 Bielefeld, Germany; fDepartment of Physics, Karlsruhe Institute of Technology, 76131 Karlsruhe, Germany; gSteinbuch Centre for Computing, Karlsruhe Institute of Technology, 76344 Eggenstein-Leopoldshafen, Germany; and hJohn von Neumann Institute for Computing, Jülich Supercomputing Centre, Forschungszentrum Jülich, 52425 Jülich, Germany Edited by Richard H. Goodman, Vollum Institute, Portland, OR, and approved June 24, 2019 (received for review February 9, 2019) Nicotinamide adenine dinucleotide (NAD) provides an important The enzymes involved in these processes are sensitive to the link between metabolism and signal transduction and has emerged available NAD concentration. Therefore, NAD-dependent signal- as central hub between bioenergetics and all major cellular events. ing can act as a transmitter of changes in cellular energy ho- NAD-dependent signaling (e.g., by sirtuins and poly–adenosine meostasis, for example, to regulate gene expression or metabolic diphosphate [ADP] ribose polymerases [PARPs]) consumes consider- activity (30). able amounts of NAD. To maintain physiological functions, NAD The significance of NAD-dependent signaling for NAD ho- consumption and biosynthesis need to be carefully balanced. Using meostasis has long been underestimated. -
Synthesis and Consumption: a Focus on the PARP Family
Downloaded from genesdev.cshlp.org on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press SPECIAL SECTION: REVIEW Interplay between compartmentalized NAD+ synthesis and consumption: a focus on the PARP family Michael S. Cohen Department of Chemical Physiology and Biochemistry, Oregon Health and Science University, Portland, Oregon 97210, USA Nicotinamide adenine dinucleotide (NAD+) is an essential erate a polymer of ADP-ribose (ADPr), a process known as cofactor for redox enzymes, but also moonlights as a sub- poly-ADP-ribosylation or PARylation (more on this below) strate for signaling enzymes. When used as a substrate by (Fig. 1; Chambon et al. 1963, 1966; Fujimura et al. 1967a,b). signaling enzymes, it is consumed, necessitating the recy- Unlike NAD+-mediated redox reactions, this glycosidic cling of NAD+ consumption products (i.e., nicotinamide) cleavage reaction is irreversible and leads to the consump- via a salvage pathway in order to maintain NAD+ homeo- tion of NAD+. Consistent with this notion, in the 1970s it stasis. A major family of NAD+ consumers in mammalian was shown that NAD+ exhibits a high turnover in human cells are poly-ADP-ribose-polymerases (PARPs). PARPs cells (Rechsteiner et al. 1976). We now know that there are comprise a family of 17 enzymes in humans, 16 of which many “NAD+ consumers” (e.g., other PARP family mem- catalyze the transfer of ADP-ribose from NAD+ to macro- ber, sirtuins, etc.) beyond PARP1, which are found in molecular targets (namely, proteins, but also DNA and nearly all subcellular compartments, including the nucle- RNA). Because PARPs and the NAD+ biosynthetic en- us, cytoplasm, and mitochondria (Fig. -
Screening with an NMNAT2-MSD Platform Identifies Small Molecules
www.nature.com/scientificreports OPEN Screening with an NMNAT2-MSD platform identifies small molecules that modulate NMNAT2 levels in Received: 30 September 2016 Accepted: 30 January 2017 cortical neurons Published: 07 March 2017 Yousuf O. Ali1,2,3,4, Gillian Bradley1,5 & Hui-Chen Lu1,2,3,4,5 Nicotinamide mononucleotide adenylyl transferase 2 (NMNAT2) is a key neuronal maintenance factor and provides potent neuroprotection in numerous preclinical models of neurological disorders. NMNAT2 is significantly reduced in Alzheimer’s, Huntington’s, Parkinson’s diseases. Here we developed a Meso Scale Discovery (MSD)-based screening platform to quantify endogenous NMNAT2 in cortical neurons. The high sensitivity and large dynamic range of this NMNAT2-MSD platform allowed us to screen the Sigma LOPAC library consisting of 1280 compounds. This library had a 2.89% hit rate, with 24 NMNAT2 positive and 13 negative modulators identified. Western analysis was conducted to validate and determine the dose-dependency of identified modulators. Caffeine, one identified NMNAT2 positive-modulator, when systemically administered restored NMNAT2 expression in rTg4510 tauopathy mice to normal levels. We confirmed in a cell culture model that four selected positive- modulators exerted NMNAT2-specific neuroprotection against vincristine-induced cell death while four selected NMNAT2 negative modulators reduced neuronal viability in an NMNAT2-dependent manner. Many of the identified NMNAT2 positive modulators are predicted to increase cAMP concentration, suggesting that neuronal NMNAT2 levels are tightly regulated by cAMP signaling. Taken together, our findings indicate that the NMNAT2-MSD platform provides a sensitive phenotypic screen to detect NMNAT2 in neurons. Optimal brain function requires that neurons respond appropriately to a range of environmental challenges. -
Nmnats, Evolutionarily Conserved Neuronal Maintenance Factors
Review NMNATs, evolutionarily conserved neuronal maintenance factors 1,2,3 2,4 2,3,4,5 Yousuf O. Ali , David Li-Kroeger , Hugo J. Bellen , 6 1,2,3,5 R. Grace Zhai , and Hui-Chen Lu 1 The Cain Foundation Laboratories, Texas Children’s Hospital, Houston, TX 77030, USA 2 Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston, TX 77030, USA 3 Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA 4 Department of Molecular and Human Genetics, and Howard Hughes Medical Institute (HHMI), Baylor College of Medicine, Houston, TX 77030, USA 5 Program in Developmental Biology and Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA 6 Department of Molecular and Cellular Pharmacology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA Proper brain function requires neuronal homeostasis A neuronal maintenance function has been attributed to over a range of environmental challenges. Neuronal NMNAT proteins, first characterized as essential enzymes activity, injury, and aging stress the nervous system, catalyzing NAD synthesis. Drosophila has a single and lead to neuronal dysfunction and degeneration. NMNAT gene, whereas mice and humans have three, Nevertheless, most organisms maintain healthy neu- NMNAT1–3, whose products differ in their kinetic proper- rons throughout life, implying the existence of active ties [2]. Drosophila NMNAT (dNMNAT) is widely distrib- maintenance mechanisms. Recent studies have revealed uted within cells [3], whereas mammalian NMNAT1–3 a key neuronal maintenance and protective function for proteins have distinct subcellular localizations [4]: nicotinamide mononucleotide adenylyl transferases NMNAT1 is localized to the nucleus, NMNAT2 is present (NMNATs). -
An Alu-Mediated Duplication in NMNAT1, Involved in NAD Biosynthesis, Causes a Novel Syndrome, SHILCA, Affecting Multiple Tissues and Organs
An Alu-mediated duplication in NMNAT1, involved in NAD biosynthesis, causes a novel syndrome, SHILCA, affecting multiple tissues and organs Nicola Bedoni1,2‡; Mathieu Quinodoz1,3,4,5‡; Michele Pinelli6,7*; Gerarda Cappuccio6,7; Annalaura Torella6,8; Vincenzo Nigro6,8; Francesco Testa9; Francesca Simonelli9; TUDP (Telethon Undiagnosed Disease Program); Marta Corton10,11; Susanna Lualdi12; Federica Lanza12; Giovanni Morana13; Carmen Ayuso10,11; Maja Di Rocco12; Mirella Filocamo12; Sandro Banfi6,8; Nicola Brunetti-Pierri6,7; Andrea Superti-Furga2‡; Carlo Rivolta3,4,5‡* 1Department of Computational Biology, University of Lausanne, Lausanne, Switzerland. 2Division of Genetic Medicine, Lausanne University Hospital, Lausanne, Switzerland. 3Department of Genetics and Genome Biology, University of Leicester, Leicester, United Kingdom. 4Institute of Molecular and Clinical Ophthalmology Basel, Basel, Switzerland. 5Department of Ophthalmology, University of Basel, Basel, Switzerland. 6Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli (Naples), Italy. 75Department of Translational Medicine, Section of Pediatrics, Federico II University, Naples, Italy. 8Medical Genetics, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Naples, Italy. 9Eye Clinic, Multidisciplinary Department of Medical, Surgical and Dental Sciences, University of Campania “Luigi Vanvitelli”, Naples, Italy. 10Department of Genetics, Instituto de Investigación Sanitaria – Fundación Jiménez Díaz, University Hospital, Universidad Autónoma de Madrid -
ADHD) Gene Networks in Children of Both African American and European American Ancestry
G C A T T A C G G C A T genes Article Rare Recurrent Variants in Noncoding Regions Impact Attention-Deficit Hyperactivity Disorder (ADHD) Gene Networks in Children of both African American and European American Ancestry Yichuan Liu 1 , Xiao Chang 1, Hui-Qi Qu 1 , Lifeng Tian 1 , Joseph Glessner 1, Jingchun Qu 1, Dong Li 1, Haijun Qiu 1, Patrick Sleiman 1,2 and Hakon Hakonarson 1,2,3,* 1 Center for Applied Genomics, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA; [email protected] (Y.L.); [email protected] (X.C.); [email protected] (H.-Q.Q.); [email protected] (L.T.); [email protected] (J.G.); [email protected] (J.Q.); [email protected] (D.L.); [email protected] (H.Q.); [email protected] (P.S.) 2 Division of Human Genetics, Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA 3 Department of Human Genetics, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA * Correspondence: [email protected]; Tel.: +1-267-426-0088 Abstract: Attention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder with poorly understood molecular mechanisms that results in significant impairment in children. In this study, we sought to assess the role of rare recurrent variants in non-European populations and outside of coding regions. We generated whole genome sequence (WGS) data on 875 individuals, Citation: Liu, Y.; Chang, X.; Qu, including 205 ADHD cases and 670 non-ADHD controls. The cases included 116 African Americans H.-Q.; Tian, L.; Glessner, J.; Qu, J.; Li, (AA) and 89 European Americans (EA), and the controls included 408 AA and 262 EA. -
1 | Page SARM1 Deficiency, Which Prevents Wallerian Degeneration
bioRxiv preprint doi: https://doi.org/10.1101/485052; this version posted December 3, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. SARM1 deficiency, which prevents Wallerian degeneration, upregulates XAF1 and accelerates prion disease Caihong Zhu#, Bei Li#, Karl Frontzek, Yingjun Liu and Adriano Aguzzi* Institute of Neuropathology, University of Zurich, Zurich, Switzerland # equal contribution * Corresponding author: Adriano Aguzzi Institute of Neuropathology, University of Zurich Schmelzbergstrasse 12, CH-8091 Zurich, Switzerland Tel: +41-44-255-2107 Email address: [email protected] Condensed title: SARM1 deficiency accelerates prion diseases Abbreviations: CNS, central nervous system; dpi, days post inoculation; MyD88, myeloid differentiation primary response gene 88; NBH, non-infectious brain homogenates; PK, proteinase K; qRT-PCR, quantitative real-time PCR; RML6, Rocky Mountain Laboratories scrapie strain passage 6; SARM1, sterile α and HEAT/armadillo motifs containing protein; XAF1, X-linked inhibitor of apoptosis-associated factor 1. 1 | Page bioRxiv preprint doi: https://doi.org/10.1101/485052; this version posted December 3, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Abstract SARM1 (sterile α and HEAT/armadillo motifs containing protein) is a member of the MyD88 (myeloid differentiation primary response gene 88) family which mediates innate immune responses. Because inactivation of SARM1 prevents various forms of axonal degeneration, we tested whether it might protect against prion-induced neurotoxicity. Instead, we found that SARM1 deficiency exacerbates the progression of prion pathogenesis. -
Nicotinamide Mononucleotide Requires SIRT3 to Improve Cardiac Function and Bioenergetics in a Friedreich’S Ataxia Cardiomyopathy Model
RESEARCH ARTICLE Nicotinamide mononucleotide requires SIRT3 to improve cardiac function and bioenergetics in a Friedreich’s ataxia cardiomyopathy model Angelical S. Martin,1,2 Dennis M. Abraham,3 Kathleen A. Hershberger,1,2 Dhaval P. Bhatt,1 Lan Mao,3 Huaxia Cui,1 Juan Liu,2 Xiaojing Liu,2 Michael J. Muehlbauer,1 Paul A. Grimsrud,1 Jason W. Locasale,1,2 R. Mark Payne,4 and Matthew D. Hirschey1,2,5 1Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center, 2Department of Pharmacology and Cancer Biology, 3Department of Medicine, Division of Cardiology and Duke Cardiovascular Physiology Core, Duke University Medical Center, Durham, North Carolina, USA. 4Department of Medicine, Division of Pediatrics, Indiana University, Indianapolis, Indiana, USA. 5Department of Medicine, Division of Endocrinology, Metabolism, & Nutrition, Duke University Medical Center, Durham, North Carolina, USA. Increasing NAD+ levels by supplementing with the precursor nicotinamide mononucleotide (NMN) improves cardiac function in multiple mouse models of disease. While NMN influences several aspects of mitochondrial metabolism, the molecular mechanisms by which increased NAD+ enhances cardiac function are poorly understood. A putative mechanism of NAD+ therapeutic action exists via activation of the mitochondrial NAD+-dependent protein deacetylase sirtuin 3 (SIRT3). We assessed the therapeutic efficacy of NMN and the role of SIRT3 in the Friedreich’s ataxia cardiomyopathy mouse model (FXN-KO). At baseline, the FXN-KO heart has mitochondrial protein hyperacetylation, reduced Sirt3 mRNA expression, and evidence of increased NAD+ salvage. Remarkably, NMN administered to FXN-KO mice restores cardiac function to near-normal levels. To determine whether SIRT3 is required for NMN therapeutic efficacy, we generated SIRT3-KO and SIRT3-KO/FXN-KO (double KO [dKO]) models.