{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T02:09:14Z","timestamp":1790820554601,"version":"4.1.0"},"reference-count":39,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2020,2,1]],"date-time":"2020-02-01T00:00:00Z","timestamp":1580515200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["PJT-156345"],"award-info":[{"award-number":["PJT-156345"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"name":"JLK Foundation","award":["Gift"],"award-info":[{"award-number":["Gift"]}]},{"name":"Jonah\u2019s Just Began Foundation","award":["Gift"],"award-info":[{"award-number":["Gift"]}]},{"name":"Sanfilippo Children\u2019s Research Foundation","award":["Gift"],"award-info":[{"award-number":["Gift"]}]},{"DOI":"10.13039\/501100001807","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de S\u00e3o Paulo","doi-asserted-by":"publisher","award":["FAPESP #2018\/17003-6"],"award-info":[{"award-number":["FAPESP #2018\/17003-6"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000828","name":"Royal Society of Medicine","doi-asserted-by":"publisher","award":["Wolfson Research Merit Award"],"award-info":[{"award-number":["Wolfson Research Merit Award"]}],"id":[{"id":"10.13039\/501100000828","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["Investigator in Science Award"],"award-info":[{"award-number":["Investigator in Science Award"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"name":"The Carol Ann Foundation","award":["Gift"],"award-info":[{"award-number":["Gift"]}]},{"name":"Angelo R. Cali &amp; Mary V. Cali Family Foundation, Inc.","award":["Gift"],"award-info":[{"award-number":["Gift"]}]},{"name":"The Vain and Harry Fish Foundation","award":["Gift"],"award-info":[{"award-number":["Gift"]}]},{"name":"The Bennett Foundation","award":["Gift"],"award-info":[{"award-number":["Gift"]}]},{"name":"Jacob Randall Foundation","award":["Gift"],"award-info":[{"award-number":["Gift"]}]},{"name":"Austrian and Japanese MPS societies","award":["Gift"],"award-info":[{"award-number":["Gift"]}]},{"name":"Nemours Funds","award":["Gift"],"award-info":[{"award-number":["Gift"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Mucopolysaccharidoses (MPS) are the group of lysosomal storage disorders caused by deficiencies of enzymes involved in the stepwise degradation of glycosaminoglycans. To identify brain pathology common for neurological MPS, we conducted a comprehensive analysis of brain cortex tissues from post-mortem autopsy materials of eight patients affected with MPS I, II, IIIA, IIIC, and IIID, and age-matched controls. Frozen brain tissues were analyzed for the abundance of glycosaminoglycans (heparan, dermatan, and keratan sulfates) by LC-MS\/MS, glycosphingolipids by normal phase HPLC, and presence of inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor superfamily member 10 (TNFSF10) by Western blotting. Fixed tissues were stained for the markers for microgliosis, astrogliosis, misfolded proteins, impaired autophagy, and GM2 ganglioside. Our results demonstrate that increase of heparan sulfate, decrease of keratan sulfate, and storage of simple monosialogangliosides 2 and 3 (GM2 and GM3) as well as the neutral glycosphingolipid, LacCer, together with neuroinflammation and neuronal accumulation of misfolded proteins are the hallmarks of brain pathology in MPS patients. These biomarkers are similar to those reported in the corresponding mouse models, suggesting that the pathological mechanism is common for all neurological MPS in humans and mice.<\/jats:p>","DOI":"10.3390\/jcm9020396","type":"journal-article","created":{"date-parts":[[2020,2,3]],"date-time":"2020-02-03T01:25:51Z","timestamp":1580693151000},"page":"396","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":70,"title":["Brain Pathology in Mucopolysaccharidoses (MPS) Patients with Neurological Forms"],"prefix":"10.3390","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0473-9665","authenticated-orcid":false,"given":"Gustavo M.","family":"Viana","sequence":"first","affiliation":[{"name":"Division of Medical Genetics, CHU Ste-Justine Research Centre, Montreal, QC H3T 1C5, Canada"},{"name":"Department of Biochemistry, Federal University of S\u00e3o Paulo (UNIFESP), S\u00e3o Paulo 04044-020, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Priestman","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Oxford, Oxford OX1 3SZ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7614-0403","authenticated-orcid":false,"given":"Frances M.","family":"Platt","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Oxford, Oxford OX1 3SZ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaukat","family":"Khan","sequence":"additional","affiliation":[{"name":"Nemours\/Alfred I. duPont Hospital for Children, Wilmington, DE 19801, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0673-2160","authenticated-orcid":false,"given":"Shunji","family":"Tomatsu","sequence":"additional","affiliation":[{"name":"Nemours\/Alfred I. duPont Hospital for Children, Wilmington, DE 19801, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6612-1062","authenticated-orcid":false,"given":"Alexey V.","family":"Pshezhetsky","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics, CHU Ste-Justine Research Centre, Montreal, QC H3T 1C5, Canada"},{"name":"Department of Biochemistry, Federal University of S\u00e3o Paulo (UNIFESP), S\u00e3o Paulo 04044-020, SP, Brazil"},{"name":"Department of Pharmacology, University of Oxford, Oxford OX1 3SZ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,2,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1001\/jama.281.3.249","article-title":"Prevalence of lysosomal storage disorders","volume":"281","author":"Meikle","year":"1999","journal-title":"JAMA"},{"key":"ref_2","first-page":"100469","article-title":"Selective screening for detection of mucopolysaccharidoses in Malaysia; A two-year study (2014\u20132016)","volume":"19","author":"Omar","year":"2019","journal-title":"Mol. Genet. Metab. Rep."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Federhen, A., Pasqualim, G., de Freitas, T.F., Gonzalez, E.A., Trapp, F., Matte, U., and Giugliani, R. (2020). Estimated birth prevalence of mucopolysaccharidoses in Brazil. Am. J. Med. Genet. A, 10.1002\/ajmg.a.61456.","DOI":"10.1002\/ajmg.a.61456"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1590\/1678-4685-gmb-2016-0268","article-title":"Relative frequency and estimated minimal frequency of Lysosomal Storage Diseases in Brazil: Report from a Reference Laboratory","volume":"40","author":"Giugliani","year":"2017","journal-title":"Genet. Mol. Biol."},{"key":"ref_5","unstructured":"Scriver, C.R., Beaudet, A.L., Sly, W.S., and Valle, D. (2001). The Mucopolysaccharidoses. The Metabolic and Molecular Basis of Inherited Disease, McGraw-Hill."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1007\/s10545-008-0838-5","article-title":"Sanfilippo syndrome: A mini-review","volume":"31","author":"Valstar","year":"2008","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_7","first-page":"100549","article-title":"The nature and impact of neurobehavioral symptoms in neuronopathic Hunter syndrome","volume":"22","author":"Eisengart","year":"2020","journal-title":"Mol. Genet. Metab. Rep."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.ymgme.2017.10.007","article-title":"Treatment of brain disease in the mucopolysaccharidoses","volume":"122S","author":"Scarpa","year":"2017","journal-title":"Mol. Genet. Metab."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1097\/00005072-199908000-00004","article-title":"Accumulation of intracellular amyloid-beta peptide (A beta 1-40) in mucopolysaccharidosis brains","volume":"58","author":"Ginsberg","year":"1999","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1007\/s00401-007-0325-3","article-title":"Mechanisms of neurodegeneration in mucopolysaccharidoses II and IIIB: analysis of human brain tissue","volume":"115","author":"Hamano","year":"2008","journal-title":"Acta Neuropathol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"8332","DOI":"10.1073\/pnas.0903223106","article-title":"Sanfilippo syndrome type B, a lysosomal storage disease, is also a tauopathy","volume":"106","author":"Ohmi","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Ohmi, K., Zhao, H.Z., and Neufeld, E.F. (2011). Defects in the medial entorhinal cortex and dentate gyrus in the mouse model of Sanfilippo syndrome type B. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0027461"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"14505","DOI":"10.1073\/pnas.96.25.14505","article-title":"Mouse model of Sanfilippo syndrome type B produced by targeted disruption of the gene encoding alpha-N-acetylglucosaminidase","volume":"96","author":"Li","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1389","DOI":"10.1093\/glycob\/9.12.1389","article-title":"A mouse model for mucopolysaccharidosis type III A (Sanfilippo syndrome)","volume":"9","author":"Bhaumik","year":"1999","journal-title":"Glycobiology"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1093\/brain\/awu355","article-title":"Neuroinflammation, mitochondrial defects and neurodegeneration in mucopolysaccharidosis III type C mouse model","volume":"138","author":"Martins","year":"2015","journal-title":"Brain"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1093\/hmg\/6.4.503","article-title":"Murine mucopolysaccharidosis type I: Targeted disruption of the murine alpha-L-iduronidase gene","volume":"6","author":"Clarke","year":"1997","journal-title":"Hum. Mol. Genet."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/j.bbr.2012.04.051","article-title":"Evidence of a progressive motor dysfunction in Mucopolysaccharidosis type I mice","volume":"233","author":"Baldo","year":"2012","journal-title":"Behav. Brain Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/j.brainres.2006.01.008","article-title":"Long-term memory for aversive training is impaired in Idua(-\/-) mice, a genetic model of mucopolysaccharidosis type I","volume":"1076","author":"Reolon","year":"2006","journal-title":"Brain Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1016\/j.ymgme.2018.08.003","article-title":"Anatomical changes and pathophysiology of the brain in mucopolysaccharidosis disorders","volume":"125","author":"Bigger","year":"2018","journal-title":"Mol. Genet. Metab."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1016\/j.ab.2004.03.051","article-title":"Analysis of fluorescently labeled glycosphingolipid-derived oligosaccharides following ceramide glycanase digestion and anthranilic acid labeling","volume":"331","author":"Neville","year":"2004","journal-title":"Anal. Biochem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1016\/0005-2760(73)90055-6","article-title":"A new procedure for the extraction, purification and fractionation of brain gangliosides","volume":"296","author":"Tettamanti","year":"1973","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_22","first-page":"1511","article-title":"Chimeric anti-ganglioside GM2 antibody with antitumor activity","volume":"54","author":"Nakamura","year":"1994","journal-title":"Cancer Res."},{"key":"ref_23","first-page":"100455","article-title":"Biomarkers in patients with mucopolysaccharidosis type II and IV","volume":"19","author":"Fujitsuka","year":"2019","journal-title":"Mol. Genet. Metab. Rep."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1016\/j.ymgme.2009.12.003","article-title":"Upregulation of elastase activity in aorta in mucopolysaccharidosis I and VII dogs may be due to increased cytokine expression","volume":"99","author":"Metcalf","year":"2010","journal-title":"Mol. Genet. Metab."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1016\/j.bbmt.2005.12.026","article-title":"Inflammatory cytokines and the development of pulmonary complications after allogeneic hematopoietic cell transplantation in patients with inherited metabolic storage disorders","volume":"12","author":"Kharbanda","year":"2006","journal-title":"Biol. Blood Marrow Transplant."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2017","DOI":"10.1007\/s00018-016-2164-7","article-title":"Clinical perspectives of TRAIL: Insights into central nervous system disorders","volume":"73","author":"Tisato","year":"2016","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1007\/s00109-009-0484-x","article-title":"Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) in central nervous system inflammation","volume":"87","author":"Hoffmann","year":"2009","journal-title":"J. Mol. Med. (Berlin)"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1042\/EBC20170055","article-title":"Dysregulation of autophagy as a common mechanism in lysosomal storage diseases","volume":"61","author":"Seranova","year":"2017","journal-title":"Essays Biochem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1016\/j.ymgme.2006.11.006","article-title":"Lysosomal accumulation of SCMAS (subunit c of mitochondrial ATP synthase) in neurons of the mouse model of mucopolysaccharidosis III B","volume":"90","author":"Ryazantsev","year":"2007","journal-title":"Mol. Genet. Metab."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1007\/s10545-005-5673-3","article-title":"Keratan sulphate levels in mucopolysaccharidoses and mucolipidoses","volume":"28","author":"Tomatsu","year":"2005","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"655","DOI":"10.3390\/metabo4030655","article-title":"Establishment of glycosaminoglycan assays for mucopolysaccharidoses","volume":"4","author":"Tomatsu","year":"2014","journal-title":"Metabolites"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1007\/s10545-012-9522-x","article-title":"Assessment of bone dysplasia by micro-CT and glycosaminoglycan levels in mouse models for mucopolysaccharidosis type I, IIIA, IVA, and VII","volume":"36","author":"Rowan","year":"2013","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_33","first-page":"19","article-title":"Newborn screening and diagnosis of mucopolysaccharidoses: Application of tandem mass spectrometry","volume":"24","author":"Tomatsu","year":"2014","journal-title":"Nihon Masu Sukuriningu Gakkai Shi"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1016\/j.bbamcr.2008.11.014","article-title":"Secondary lipid accumulation in lysosomal disease","volume":"1793","author":"Walkley","year":"2009","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1481","DOI":"10.1093\/hmg\/ddr584","article-title":"GM130 gain-of-function induces cell pathology in a model of lysosomal storage disease","volume":"21","author":"Roy","year":"2012","journal-title":"Hum. Mol. Genet."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1016\/S0962-8924(02)02399-1","article-title":"Endocytosis and sorting of glycosphingolipids in sphingolipid storage disease","volume":"12","author":"Marks","year":"2002","journal-title":"Trends Cell Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1016\/j.semcdb.2004.03.004","article-title":"Glycosphingolipids in endocytic membrane transport","volume":"15","author":"Sillence","year":"2004","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Wilkinson, F.L., Holley, R.J., Langford-Smith, K.J., Badrinath, S., Liao, A., Langford-Smith, A., Cooper, J.D., Jones, S.A., Wraith, J.E., and Wynn, R.F. (2012). Neuropathology in mouse models of mucopolysaccharidosis type I, IIIA and IIIB. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0035787"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Ausseil, J., Desmaris, N., Bigou, S., Attali, R., Corbineau, S., Vitry, S., Parent, M., Cheillan, D., Fuller, M., and Maire, I. (2008). Early neurodegeneration progresses independently of microglial activation by heparan sulfate in the brain of mucopolysaccharidosis IIIB mice. PLoS ONE, 3.","DOI":"10.1371\/journal.pone.0002296"}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/9\/2\/396\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T08:53:48Z","timestamp":1760172828000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/9\/2\/396"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,2,1]]},"references-count":39,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2020,2]]}},"alternative-id":["jcm9020396"],"URL":"https:\/\/doi.org\/10.3390\/jcm9020396","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,2,1]]}}}