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      RNA Sequence Analysis of Human Huntington Disease Brain Reveals an Extensive Increase in Inflammatory and Developmental Gene Expression

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          Abstract

          Huntington’s Disease (HD) is a devastating neurodegenerative disorder that is caused by an expanded CAG trinucleotide repeat in the Huntingtin ( HTT) gene. Transcriptional dysregulation in the human HD brain has been documented but is incompletely understood. Here we present a genome-wide analysis of mRNA expression in human prefrontal cortex from 20 HD and 49 neuropathologically normal controls using next generation high-throughput sequencing. Surprisingly, 19% (5,480) of the 28,087 confidently detected genes are differentially expressed (FDR<0.05) and are predominantly up-regulated. A novel hypothesis-free geneset enrichment method that dissects large gene lists into functionally and transcriptionally related groups discovers that the differentially expressed genes are enriched for immune response, neuroinflammation, and developmental genes. Markers for all major brain cell types are observed, suggesting that HD invokes a systemic response in the brain area studied. Unexpectedly, the most strongly differentially expressed genes are a homeotic gene set (represented by Hox and other homeobox genes), that are almost exclusively expressed in HD, a profile not widely implicated in HD pathogenesis. The significance of transcriptional changes of developmental processes in the HD brain is poorly understood and warrants further investigation. The role of inflammation and the significance of non-neuronal involvement in HD pathogenesis suggest anti-inflammatory therapeutics may offer important opportunities in treating HD.

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          Gene Ontology: tool for the unification of biology

          Michael Ashburner, Catherine A. Ball, Judith Blake … (2002)
          Genomic sequencing has made it clear that a large fraction of the genes specifying the core biological functions are shared by all eukaryotes. Knowledge of the biological role of such shared proteins in one organism can often be transferred to other organisms. The goal of the Gene Ontology Consortium is to produce a dynamic, controlled vocabulary that can be applied to all eukaryotes even as knowledge of gene and protein roles in cells is accumulating and changing. To this end, three independent ontologies accessible on the World-Wide Web (http://www.geneontology.org) are being constructed: biological process, molecular function and cellular component.
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            The calpain system.

            DARREL E. GOLL, VALERY THOMPSON, HONGQI LI … (2003)
            The calpain system originally comprised three molecules: two Ca2+-dependent proteases, mu-calpain and m-calpain, and a third polypeptide, calpastatin, whose only known function is to inhibit the two calpains. Both mu- and m-calpain are heterodimers containing an identical 28-kDa subunit and an 80-kDa subunit that shares 55-65% sequence homology between the two proteases. The crystallographic structure of m-calpain reveals six "domains" in the 80-kDa subunit: 1). a 19-amino acid NH2-terminal sequence; 2). and 3). two domains that constitute the active site, IIa and IIb; 4). domain III; 5). an 18-amino acid extended sequence linking domain III to domain IV; and 6). domain IV, which resembles the penta EF-hand family of polypeptides. The single calpastatin gene can produce eight or more calpastatin polypeptides ranging from 17 to 85 kDa by use of different promoters and alternative splicing events. The physiological significance of these different calpastatins is unclear, although all bind to three different places on the calpain molecule; binding to at least two of the sites is Ca2+ dependent. Since 1989, cDNA cloning has identified 12 additional mRNAs in mammals that encode polypeptides homologous to domains IIa and IIb of the 80-kDa subunit of mu- and m-calpain, and calpain-like mRNAs have been identified in other organisms. The molecules encoded by these mRNAs have not been isolated, so little is known about their properties. How calpain activity is regulated in cells is still unclear, but the calpains ostensibly participate in a variety of cellular processes including remodeling of cytoskeletal/membrane attachments, different signal transduction pathways, and apoptosis. Deregulated calpain activity following loss of Ca2+ homeostasis results in tissue damage in response to events such as myocardial infarcts, stroke, and brain trauma.
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              Biology of oligodendrocyte and myelin in the mammalian central nervous system.

              N Baumann, D. Pham-Dinh (2001)
              Oligodendrocytes, the myelin-forming cells of the central nervous system (CNS), and astrocytes constitute macroglia. This review deals with the recent progress related to the origin and differentiation of the oligodendrocytes, their relationships to other neural cells, and functional neuroglial interactions under physiological conditions and in demyelinating diseases. One of the problems in studies of the CNS is to find components, i.e., markers, for the identification of the different cells, in intact tissues or cultures. In recent years, specific biochemical, immunological, and molecular markers have been identified. Many components specific to differentiating oligodendrocytes and to myelin are now available to aid their study. Transgenic mice and spontaneous mutants have led to a better understanding of the targets of specific dys- or demyelinating diseases. The best examples are the studies concerning the effects of the mutations affecting the most abundant protein in the central nervous myelin, the proteolipid protein, which lead to dysmyelinating diseases in animals and human (jimpy mutation and Pelizaeus-Merzbacher disease or spastic paraplegia, respectively). Oligodendrocytes, as astrocytes, are able to respond to changes in the cellular and extracellular environment, possibly in relation to a glial network. There is also a remarkable plasticity of the oligodendrocyte lineage, even in the adult with a certain potentiality for myelin repair after experimental demyelination or human diseases.
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                Author and article information

                Contributors
                Hiroyoshi Ariga: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, CA USA )
                ISSN (Electronic): 1932-6203
                Publication date (Electronic): 4 December 2015
                Publication date Collection: 2015
                Volume: 10
                Issue: 12
                Electronic Location Identifier: e0143563
                Affiliations
                [1 ]Department of Neurology, Boston University School of Medicine, Boston, MA, United States of America
                [2 ]Bioinformatics Program, Boston University, Boston, MA, United States of America
                [3 ]Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States of America
                [4 ]Friedman Brain Institute, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
                [5 ]Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, MA, United States of America
                [6 ]Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA, United States of America
                [7 ]Genome Science Institute, Boston University School of Medicine, Boston, MA, United States of America
                Hokkaido University, JAPAN
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: AL J-FC SA ZW RHM. Performed the experiments: AL AGH VL JB RHM. Analyzed the data: AL JCL. Contributed reagents/materials/analysis tools: TCH MEM JFG RHM. Wrote the paper: AL AGH JCL RHM.

                Article
                Publisher ID: PONE-D-15-05118
                DOI: 10.1371/journal.pone.0143563
                PMC ID: 4670106
                PubMed ID: 26636579
                SO-VID: 88c8a3fb-e295-4cfa-8269-e759f0d51b6a
                Copyright © © 2015 Labadorf et al
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

                History
                Date received : 3 February 2015
                Date accepted : 8 November 2015
                Page count
                Figures: 4, Tables: 7, Pages: 21
                Funding
                This work was supported by the Jerry McDonald HD Research Fund (RHM) and Public Health Service, National Institutes of Health grants, National Institute of Neurological disorders and stroke, R01-NS073947 (RHM) and R01-NS32765 (MEM) and PHY-1444389 NSF-EArly-concept Grants for Exploratory Research (EAGER). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Subject: Research Article
                Custom metadata
                Data Availability All files are available from the GEO database (accession number GSE64810).

                ScienceOpen disciplines: Uncategorized
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                ScienceOpen disciplines: Uncategorized

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