Severe central nervous system demyelination in Sanfilippo disease
IntroductionChronic progressive neuroinflammation is a hallmark of neurological lysosomal storage diseases, including mucopolysaccharidosis III (MPS III or Sanfilippo disease). Since neuroinflammation is linked to white matter tract pathology, we analyzed axonal myelination and white matter density...
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Frontiers Media S.A.
2023-12-01
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| Series: | Frontiers in Molecular Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fnmol.2023.1323449/full |
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| author | Mahsa Taherzadeh Mahsa Taherzadeh Erjun Zhang Irene Londono Benjamin De Leener Benjamin De Leener Sophie Wang Jonathan D. Cooper Timothy E. Kennedy Timothy E. Kennedy Carlos R. Morales Zesheng Chen Gregory A. Lodygensky Alexey V. Pshezhetsky Alexey V. Pshezhetsky |
| author_facet | Mahsa Taherzadeh Mahsa Taherzadeh Erjun Zhang Irene Londono Benjamin De Leener Benjamin De Leener Sophie Wang Jonathan D. Cooper Timothy E. Kennedy Timothy E. Kennedy Carlos R. Morales Zesheng Chen Gregory A. Lodygensky Alexey V. Pshezhetsky Alexey V. Pshezhetsky |
| author_sort | Mahsa Taherzadeh |
| collection | DOAJ |
| description | IntroductionChronic progressive neuroinflammation is a hallmark of neurological lysosomal storage diseases, including mucopolysaccharidosis III (MPS III or Sanfilippo disease). Since neuroinflammation is linked to white matter tract pathology, we analyzed axonal myelination and white matter density in the mouse model of MPS IIIC HgsnatP304L and post-mortem brain samples of MPS III patients.MethodsBrain and spinal cord tissues of human MPS III patients, 6-month-old HgsnatP304L mice and age- and sex-matching wild type mice were analyzed by immunofluorescence to assess levels of myelin-associated proteins, primary and secondary storage materials, and levels of microgliosis. Corpus callosum (CC) region was studied by transmission electron microscopy to analyze axon myelination and morphology of oligodendrocytes and microglia. Mouse brains were analyzed ex vivo by high-filed MRI using Diffusion Basis Spectrum Imaging in Python-Diffusion tensor imaging algorithms.ResultsAnalyses of CC and spinal cord tissues by immunohistochemistry revealed substantially reduced levels of myelin-associated proteins including Myelin Basic Protein, Myelin Associated Glycoprotein, and Myelin Oligodendrocyte Glycoprotein. Furthermore, ultrastructural analyses revealed disruption of myelin sheath organization and reduced myelin thickness in the brains of MPS IIIC mice and human MPS IIIC patients compared to healthy controls. Oligodendrocytes (OLs) in the CC of MPS IIIC mice were scarce, while examination of the remaining cells revealed numerous enlarged lysosomes containing heparan sulfate, GM3 ganglioside or “zebra bodies” consistent with accumulation of lipids and myelin fragments. In addition, OLs contained swollen mitochondria with largely dissolved cristae, resembling those previously identified in the dysfunctional neurons of MPS IIIC mice. Ex vivo Diffusion Basis Spectrum Imaging revealed compelling signs of demyelination (26% increase in radial diffusivity) and tissue loss (76% increase in hindered diffusivity) in CC of MPS IIIC mice.DiscussionOur findings demonstrate an important role for white matter injury in the pathophysiology of MPS III. This study also defines specific parameters and brain regions for MRI analysis and suggests that it may become a crucial non-invasive method to evaluate disease progression and therapeutic response. |
| first_indexed | 2024-03-08T23:57:08Z |
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| language | English |
| last_indexed | 2024-03-08T23:57:08Z |
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| spelling | doaj.art-cafc015daf404af5b7297df4d90ee2402023-12-13T04:34:19ZengFrontiers Media S.A.Frontiers in Molecular Neuroscience1662-50992023-12-011610.3389/fnmol.2023.13234491323449Severe central nervous system demyelination in Sanfilippo diseaseMahsa Taherzadeh0Mahsa Taherzadeh1Erjun Zhang2Irene Londono3Benjamin De Leener4Benjamin De Leener5Sophie Wang6Jonathan D. Cooper7Timothy E. Kennedy8Timothy E. Kennedy9Carlos R. Morales10Zesheng Chen11Gregory A. Lodygensky12Alexey V. Pshezhetsky13Alexey V. Pshezhetsky14Department of Pediatrics, Centre Hospitalier Universitaire (CHU) Sainte-Justine Research Centre, University of Montreal, Montreal, QC, CanadaDepartment of Anatomy and Cell Biology, McGill University, Montreal, QC, CanadaDepartment of Pediatrics, Centre Hospitalier Universitaire (CHU) Sainte-Justine Research Centre, University of Montreal, Montreal, QC, CanadaDepartment of Pediatrics, Centre Hospitalier Universitaire (CHU) Sainte-Justine Research Centre, University of Montreal, Montreal, QC, CanadaDepartment of Pediatrics, Centre Hospitalier Universitaire (CHU) Sainte-Justine Research Centre, University of Montreal, Montreal, QC, CanadaNeuroPoly Lab, Institute of Biomedical Engineering, Department of Computer Engineering and Software Engineering, École Polytechnique de Montréal, Montreal, QC, CanadaPediatric Storage Disorders Laboratory (PSDL), Departments of Pediatrics, Genetics and Neurology, Washington University School of Medicine, St. Louis, MO, United StatesPediatric Storage Disorders Laboratory (PSDL), Departments of Pediatrics, Genetics and Neurology, Washington University School of Medicine, St. Louis, MO, United StatesDepartment of Anatomy and Cell Biology, McGill University, Montreal, QC, CanadaDepartment of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, CanadaDepartment of Anatomy and Cell Biology, McGill University, Montreal, QC, CanadaDepartment of Pediatrics, Centre Hospitalier Universitaire (CHU) Sainte-Justine Research Centre, University of Montreal, Montreal, QC, CanadaDepartment of Pediatrics, Centre Hospitalier Universitaire (CHU) Sainte-Justine Research Centre, University of Montreal, Montreal, QC, CanadaDepartment of Pediatrics, Centre Hospitalier Universitaire (CHU) Sainte-Justine Research Centre, University of Montreal, Montreal, QC, CanadaDepartment of Anatomy and Cell Biology, McGill University, Montreal, QC, CanadaIntroductionChronic progressive neuroinflammation is a hallmark of neurological lysosomal storage diseases, including mucopolysaccharidosis III (MPS III or Sanfilippo disease). Since neuroinflammation is linked to white matter tract pathology, we analyzed axonal myelination and white matter density in the mouse model of MPS IIIC HgsnatP304L and post-mortem brain samples of MPS III patients.MethodsBrain and spinal cord tissues of human MPS III patients, 6-month-old HgsnatP304L mice and age- and sex-matching wild type mice were analyzed by immunofluorescence to assess levels of myelin-associated proteins, primary and secondary storage materials, and levels of microgliosis. Corpus callosum (CC) region was studied by transmission electron microscopy to analyze axon myelination and morphology of oligodendrocytes and microglia. Mouse brains were analyzed ex vivo by high-filed MRI using Diffusion Basis Spectrum Imaging in Python-Diffusion tensor imaging algorithms.ResultsAnalyses of CC and spinal cord tissues by immunohistochemistry revealed substantially reduced levels of myelin-associated proteins including Myelin Basic Protein, Myelin Associated Glycoprotein, and Myelin Oligodendrocyte Glycoprotein. Furthermore, ultrastructural analyses revealed disruption of myelin sheath organization and reduced myelin thickness in the brains of MPS IIIC mice and human MPS IIIC patients compared to healthy controls. Oligodendrocytes (OLs) in the CC of MPS IIIC mice were scarce, while examination of the remaining cells revealed numerous enlarged lysosomes containing heparan sulfate, GM3 ganglioside or “zebra bodies” consistent with accumulation of lipids and myelin fragments. In addition, OLs contained swollen mitochondria with largely dissolved cristae, resembling those previously identified in the dysfunctional neurons of MPS IIIC mice. Ex vivo Diffusion Basis Spectrum Imaging revealed compelling signs of demyelination (26% increase in radial diffusivity) and tissue loss (76% increase in hindered diffusivity) in CC of MPS IIIC mice.DiscussionOur findings demonstrate an important role for white matter injury in the pathophysiology of MPS III. This study also defines specific parameters and brain regions for MRI analysis and suggests that it may become a crucial non-invasive method to evaluate disease progression and therapeutic response.https://www.frontiersin.org/articles/10.3389/fnmol.2023.1323449/fullmucopolysaccharidosisoligodendrocytemyelinationlysosomal storageGM3 gangliosidediffusion basis spectrum imaging |
| spellingShingle | Mahsa Taherzadeh Mahsa Taherzadeh Erjun Zhang Irene Londono Benjamin De Leener Benjamin De Leener Sophie Wang Jonathan D. Cooper Timothy E. Kennedy Timothy E. Kennedy Carlos R. Morales Zesheng Chen Gregory A. Lodygensky Alexey V. Pshezhetsky Alexey V. Pshezhetsky Severe central nervous system demyelination in Sanfilippo disease Frontiers in Molecular Neuroscience mucopolysaccharidosis oligodendrocyte myelination lysosomal storage GM3 ganglioside diffusion basis spectrum imaging |
| title | Severe central nervous system demyelination in Sanfilippo disease |
| title_full | Severe central nervous system demyelination in Sanfilippo disease |
| title_fullStr | Severe central nervous system demyelination in Sanfilippo disease |
| title_full_unstemmed | Severe central nervous system demyelination in Sanfilippo disease |
| title_short | Severe central nervous system demyelination in Sanfilippo disease |
| title_sort | severe central nervous system demyelination in sanfilippo disease |
| topic | mucopolysaccharidosis oligodendrocyte myelination lysosomal storage GM3 ganglioside diffusion basis spectrum imaging |
| url | https://www.frontiersin.org/articles/10.3389/fnmol.2023.1323449/full |
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