Brain Pathology in Mucopolysaccharidoses (MPS) Patients with Neurological Forms
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-mort...
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doaj-578cbfc90027421a85ee3cea13ddfa152020-11-25T01:45:51ZengMDPI AGJournal of Clinical Medicine2077-03832020-02-019239610.3390/jcm9020396jcm9020396Brain Pathology in Mucopolysaccharidoses (MPS) Patients with Neurological FormsGustavo M. Viana0David A. Priestman1Frances M. Platt2Shaukat Khan3Shunji Tomatsu4Alexey V. Pshezhetsky5Division of Medical Genetics, CHU Ste-Justine Research Centre, Montreal, QC H3T 1C5, CanadaDepartment of Pharmacology, University of Oxford, Oxford OX1 3SZ, UKDepartment of Pharmacology, University of Oxford, Oxford OX1 3SZ, UKNemours/Alfred I. duPont Hospital for Children, Wilmington, DE 19801, USANemours/Alfred I. duPont Hospital for Children, Wilmington, DE 19801, USADivision of Medical Genetics, CHU Ste-Justine Research Centre, Montreal, QC H3T 1C5, CanadaMucopolysaccharidoses (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.https://www.mdpi.com/2077-0383/9/2/396mucopolysaccharidosisbrain pathologyneuroinflammationglycosaminoglycansglycosphingolipidsprotein misfolding |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Gustavo M. Viana David A. Priestman Frances M. Platt Shaukat Khan Shunji Tomatsu Alexey V. Pshezhetsky |
spellingShingle |
Gustavo M. Viana David A. Priestman Frances M. Platt Shaukat Khan Shunji Tomatsu Alexey V. Pshezhetsky Brain Pathology in Mucopolysaccharidoses (MPS) Patients with Neurological Forms Journal of Clinical Medicine mucopolysaccharidosis brain pathology neuroinflammation glycosaminoglycans glycosphingolipids protein misfolding |
author_facet |
Gustavo M. Viana David A. Priestman Frances M. Platt Shaukat Khan Shunji Tomatsu Alexey V. Pshezhetsky |
author_sort |
Gustavo M. Viana |
title |
Brain Pathology in Mucopolysaccharidoses (MPS) Patients with Neurological Forms |
title_short |
Brain Pathology in Mucopolysaccharidoses (MPS) Patients with Neurological Forms |
title_full |
Brain Pathology in Mucopolysaccharidoses (MPS) Patients with Neurological Forms |
title_fullStr |
Brain Pathology in Mucopolysaccharidoses (MPS) Patients with Neurological Forms |
title_full_unstemmed |
Brain Pathology in Mucopolysaccharidoses (MPS) Patients with Neurological Forms |
title_sort |
brain pathology in mucopolysaccharidoses (mps) patients with neurological forms |
publisher |
MDPI AG |
series |
Journal of Clinical Medicine |
issn |
2077-0383 |
publishDate |
2020-02-01 |
description |
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. |
topic |
mucopolysaccharidosis brain pathology neuroinflammation glycosaminoglycans glycosphingolipids protein misfolding |
url |
https://www.mdpi.com/2077-0383/9/2/396 |
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