{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,25]],"date-time":"2026-04-25T02:39:35Z","timestamp":1777084775601,"version":"3.51.4"},"reference-count":44,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2022,11,3]],"date-time":"2022-11-03T00:00:00Z","timestamp":1667433600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Cure Tay-Sachs Foundation","award":["CTSF-361124"],"award-info":[{"award-number":["CTSF-361124"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Sandhoff disease (SD) is a fatal neurodegenerative disorder belonging to the family of diseases called GM2 Gangliosidosis. There is no curative treatment of SD. The molecular pathogenesis of SD is still unclear though it is clear that the pathology initiates with the build-up of ganglioside followed by microglial activation, inflammation, demyelination and apoptosis, leading to massive neuronal loss. In this article, we explored the expression profile of selected immune and myelination associated transcripts (Wfdc17, Ccl3, Lyz2, Fa2h, Mog and Ugt8a) at 5-, 10- and 16-weeks, representing young, pre-symptomatic and late stages of the SD mice. We found that immune system related genes (Wfdc17, Ccl3, Lyz2) are significantly upregulated by several fold at all ages in Hexb-KO mice relative to Hexb-het mice, while the difference in the expression levels of myelination related genes is not statistically significant. There is an age-dependent significant increase in expression of microglial\/pro-inflammatory genes, from 5-weeks to the near humane end-point, i.e., 16-week time point; while the expression of those genes involved in myelination decreases slightly or remains unchanged. Future studies warrant use of new high-throughput gene expression modalities (such as 10X genomics) to delineate the underlying pathogenesis in SD by detecting gene expression changes in specific neuronal cell types and thus, paving the way for rational and precise therapeutic modalities.<\/jats:p>","DOI":"10.3390\/genes13112020","type":"journal-article","created":{"date-parts":[[2022,11,3]],"date-time":"2022-11-03T03:53:07Z","timestamp":1667447587000},"page":"2020","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Gene Expression Profile in the Sandhoff Mouse Brain with Progression of Age"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1331-1951","authenticated-orcid":false,"given":"Kshitiz","family":"Singh","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Queen\u2019s University, Kingston, ON K7L 3N6, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brianna M.","family":"Quinville","sequence":"additional","affiliation":[{"name":"Centre for Neuroscience Studies, Queen\u2019s University, Kingston, ON K7L 3N6, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Melissa","family":"Mitchell","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Queen\u2019s University, Kingston, ON K7L 3N6, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhilin","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Queen\u2019s University, Kingston, ON K7L 3N6, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jagdeep S.","family":"Walia","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Queen\u2019s University, Kingston, ON K7L 3N6, Canada"},{"name":"Centre for Neuroscience Studies, Queen\u2019s University, Kingston, ON K7L 3N6, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"10195","DOI":"10.1523\/JNEUROSCI.0822-13.2013","article-title":"Gangliosides and gangliosidoses: Principles of molecular and metabolic pathogenesis","volume":"33","author":"Sandhoff","year":"2013","journal-title":"J. Neurosci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"554","DOI":"10.2183\/pjab.88.554","article-title":"My Journey into the World of Sphingolipids and Sphingolipidoses","volume":"88","author":"Sandhoff","year":"2012","journal-title":"Proc. Jpn. Acad. Ser. B Phys. Biol. Sci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/0925-4439(92)90031-H","article-title":"Characterization of Two HEXB Gene Mutations in Argentinean Patients with Sandhoff Disease","volume":"1180","author":"Brown","year":"1992","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1016\/j.jmb.2006.04.004","article-title":"Crystallographic Structure of Human \u03b2-Hexosaminidase A: Interpretation of Tay-Sachs Mutations and Loss of GM2 Ganglioside Hydrolysis","volume":"359","author":"Lemieux","year":"2006","journal-title":"J. Mol. Biol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1017\/S0317167100032583","article-title":"Biochemistry and genetics of Tay-Sachs disease","volume":"18","author":"Gravel","year":"1991","journal-title":"Can. J. Neurol. Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1046\/j.1365-2990.2002.00422.x","article-title":"Glycosphingolipid Lysosomal Storage Diseases: Therapy and Pathogenesis","volume":"28","author":"Jeyakumar","year":"2002","journal-title":"Neuropathol. Appl. Neurobiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"68","DOI":"10.2174\/1566523218666180404162622","article-title":"Genetics and Therapies for GM2 Gangliosidosis","volume":"18","author":"Zaccariotto","year":"2018","journal-title":"Curr. Gene Ther."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1002\/ana.22262","article-title":"Highly Phosphomannosylated Enzyme Replacement Therapy for GM2 Gangliosidosis","volume":"69","author":"Tsuji","year":"2011","journal-title":"Ann. Neurol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1495","DOI":"10.1016\/j.ymthe.2019.05.018","article-title":"Substrate Reduction Therapy for Sandhoff Disease through Inhibition of Glucosylceramide Synthase Activity","volume":"27","author":"Marshall","year":"2019","journal-title":"Mol. Ther."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"262","DOI":"10.2174\/1566523221666210916153051","article-title":"Treatment of GM2 Gangliosidosis in Adult Sandhoff Mice Using an Intravenous Self-Complementary Hexosaminidase Vector","volume":"22","author":"Osmon","year":"2022","journal-title":"Curr. Gene Ther."},{"key":"ref_11","first-page":"122","article-title":"Functionality of a Bicistronic Construction Containing HEXA and HEXB Genes Encoding \u03b2-Hexosaminidase A for Cell-Mediated Therapy of GM2 Gangliosidoses","volume":"17","author":"Shaimardanova","year":"2021","journal-title":"Neural Regen. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1089\/hum.2017.163","article-title":"Adeno-Associated Virus Gene Therapy in a Sheep Model of Tay-Sachs Disease","volume":"29","author":"Randle","year":"2018","journal-title":"Hum. Gene Ther."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"10954","DOI":"10.1073\/pnas.97.20.10954","article-title":"Microglial Activation Precedes Acute Neurodegeneration in Sandhoff Disease and Is Suppressed by Bone Marrow Transplantation","volume":"97","author":"Wada","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1343","DOI":"10.1093\/hmg\/11.11.1343","article-title":"Molecular Pathophysiology in Tay-Sachs and Sandhoff Diseases as Revealed by Gene Expression Profiling","volume":"11","author":"Myerowitz","year":"2002","journal-title":"Hum. Mol. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1038\/nrm1423","article-title":"The Cell Biology of Lysosomal Storage Disorders","volume":"5","author":"Futerman","year":"2004","journal-title":"Nat. Rev. Mol. Cell. Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"962","DOI":"10.1097\/WNR.0000000000001060","article-title":"Improvement in Dysmyelination by the Inhibition of Microglial Activation in a Mouse Model of Sandhoff Disease","volume":"29","author":"Ogawa","year":"2018","journal-title":"Neuroreport"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"D605","DOI":"10.1093\/nar\/gkaa1074","article-title":"The STRING Database in 2021: Customizable Protein-Protein Networks, and Functional Characterization of User-Uploaded Gene\/Measurement Sets","volume":"49","author":"Szklarczyk","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1016\/j.tibtech.2018.12.002","article-title":"The Ultimate QPCR Experiment: Producing Publication Quality, Reproducible Data the First Time","volume":"37","author":"Taylor","year":"2019","journal-title":"Trends Biotechnol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"40518","DOI":"10.1038\/srep40518","article-title":"FcR\u03b3-Dependent Immune Activation Initiates Astrogliosis during the Asymptomatic Phase of Sandhoff Disease Model Mice","volume":"7","author":"Ogawa","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"249","DOI":"10.3389\/fimmu.2015.00249","article-title":"Microglia Versus Myeloid Cell Nomenclature during Brain Inflammation","volume":"6","author":"Greter","year":"2015","journal-title":"Front. Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1359","DOI":"10.1038\/s41593-018-0242-x","article-title":"Microglia in neurodegeneration","volume":"21","author":"Hickman","year":"2018","journal-title":"Nat. Neurosci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1016\/j.brainres.2015.08.031","article-title":"How microglia kill neurons","volume":"1628","author":"Brown","year":"2015","journal-title":"Brain Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"974","DOI":"10.1093\/brain\/awg089","article-title":"Central Nervous System Inflammation Is a Hallmark of Pathogenesis in Mouse Models of GM1 and GM2 Gangliosidosis","volume":"126","author":"Jeyakumar","year":"2003","journal-title":"Brain"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1939","DOI":"10.1084\/jem.167.6.1939","article-title":"Cloning and Characterization of a CDNA for Murine Macrophage Inflammatory Protein (MIP), a Novel Monokine with Inflammatory and Chemokinetic Properties","volume":"167","author":"Davatelis","year":"1988","journal-title":"J. Exp. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1882","DOI":"10.1016\/j.biocel.2003.10.019","article-title":"Macrophage inflammatory protein-1","volume":"36","author":"Maurer","year":"2004","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2565","DOI":"10.1096\/fasebj.3.14.2687068","article-title":"Macrophage Inflammatory Proteins 1 and 2: Members of a Novel Superfamily of Cytokines","volume":"3","author":"Wolpe","year":"1989","journal-title":"FASEB J."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"8425","DOI":"10.1073\/pnas.0400625101","article-title":"Deletion of Macrophage-Inflammatory Protein 1 Alpha Retards Neurodegeneration in Sandhoff Disease Mice","volume":"101","author":"Wu","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1186\/1742-2094-9-15","article-title":"Constitutive Activity of NF-Kappa B in Myeloid Cells Drives Pathogenicity of Monocytes and Macrophages during Autoimmune Neuroinflammation","volume":"9","author":"Ellrichmann","year":"2012","journal-title":"J. Neuroinflamm."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"6232","DOI":"10.1073\/pnas.85.17.6232","article-title":"Mouse Lysozyme M Gene: Isolation, Characterization, and Expression Studies","volume":"85","author":"Cross","year":"1988","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1016\/j.bbadis.2015.09.019","article-title":"Genetic Manipulation of Microglia during Brain Development and Disease","volume":"1862","author":"Wieghofer","year":"2016","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"5146","DOI":"10.1038\/s41598-018-22872-y","article-title":"Diversity of innate immune cell subsets across spatial and temporal scales in an EAE mouse model","volume":"8","author":"Caravagna","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Ragland, S.A., and Criss, A.K. (2017). From Bacterial Killing to Immune Modulation: Recent Insights into the Functions of Lysozyme. PLoS Pathog., 13.","DOI":"10.1371\/journal.ppat.1006512"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1456","DOI":"10.1126\/science.1202529","article-title":"Synaptic Pruning by Microglia Is Necessary for Normal Brain Development","volume":"333","author":"Paolicelli","year":"2011","journal-title":"Science"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"698","DOI":"10.3389\/fimmu.2018.00698","article-title":"Microglia and Beyond: Innate Immune Cells As Regulators of Brain Development and Behavioral Function","volume":"9","author":"Lenz","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1387","DOI":"10.1038\/nn1997","article-title":"Microglia: Active Sensor and Versatile Effector Cells in the Normal and Pathologic Brain","volume":"10","author":"Hanisch","year":"2007","journal-title":"Nat. Neurosci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3379","DOI":"10.4049\/jimmunol.0903300","article-title":"The Novel Activated Microglia\/Macrophage WAP Domain Protein, AMWAP, Acts as a Counter-Regulator of Proinflammatory Response","volume":"185","author":"Karlstetter","year":"2010","journal-title":"J. Immunol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1186\/s12974-015-0296-6","article-title":"Activated Microglia\/Macrophage Whey Acidic Protein (AMWAP) Inhibits NF\u03baB Signaling and Induces a Neuroprotective Phenotype in Microglia","volume":"12","author":"Aslanidis","year":"2015","journal-title":"J. Neuroinflam."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1153","DOI":"10.1152\/physrev.00058.2017","article-title":"The UDP-Glycosyltransferase (UGT) Superfamily: New Members, New Functions, and Novel Paradigms","volume":"99","author":"Meech","year":"2019","journal-title":"Physiol. Rev."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"13280","DOI":"10.1073\/pnas.93.23.13280","article-title":"Functional Breakdown of the Lipid Bilayer of the Myelin Membrane in Central and Peripheral Nervous System by Disrupted Galactocerebroside Synthesis","volume":"93","author":"Bosio","year":"1996","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1194\/jlr.M700400-JLR200","article-title":"FA2H Is Responsible for the Formation of 2-Hydroxy Galactolipids in Peripheral Nervous System Myelin","volume":"49","author":"Maldonado","year":"2008","journal-title":"J. Lipid. Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"7990","DOI":"10.1073\/pnas.90.17.7990","article-title":"Myelin\/Oligodendrocyte Glycoprotein Is a Member of a Subset of the Immunoglobulin Superfamily Encoded within the Major Histocompatibility Complex","volume":"90","year":"1993","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_42","first-page":"443","article-title":"Augmentation of Demyelination in Rat Acute Allergic Encephalomyelitis by Circulating Mouse Monoclonal Antibodies Directed against a Myelin\/Oligodendrocyte Glycoprotein","volume":"130","author":"Linington","year":"1988","journal-title":"Am. J. Pathol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"529","DOI":"10.3389\/fimmu.2017.00529","article-title":"Myelin Oligodendrocyte Glycoprotein: Deciphering a Target in Inflammatory Demyelinating Diseases","volume":"8","author":"Peschl","year":"2017","journal-title":"Front. Immunol."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Ambrosius, W., Michalak, S., Kozubski, W., and Kalinowska, A. (2020). Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease: Current Insights into the Disease Pathophysiology, Diagnosis and Management. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22010100"}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/13\/11\/2020\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:09:46Z","timestamp":1760144986000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/13\/11\/2020"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,3]]},"references-count":44,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2022,11]]}},"alternative-id":["genes13112020"],"URL":"https:\/\/doi.org\/10.3390\/genes13112020","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,3]]}}}