Severe central nervous system demyelination in Sanfilippo disease

Mahsa Taherzadeh; Erjun Zhang; Irene Londono; Benjamin De Leener; Sophie Wang; Jonathan D Cooper; Timothy E Kennedy; Carlos R Morales; Zesheng Chen; Gregory A Lodygensky; Alexey V Pshezhetsky

doi:10.3389/fnmol.2023.1323449

Severe central nervous system demyelination in Sanfilippo disease

Front Mol Neurosci. 2023 Dec 13:16:1323449. doi: 10.3389/fnmol.2023.1323449. eCollection 2023.

Authors

Mahsa Taherzadeh^{1

2}, Erjun Zhang¹, Irene Londono¹, Benjamin De Leener^{1

3}, Sophie Wang⁴, Jonathan D Cooper⁴, Timothy E Kennedy^{2

5}, Carlos R Morales², Zesheng Chen¹, Gregory A Lodygensky¹, Alexey V Pshezhetsky^{1

2}

Affiliations

¹ Department of Pediatrics, Centre Hospitalier Universitaire (CHU) Sainte-Justine Research Centre, University of Montreal, Montreal, QC, Canada.
² Department of Anatomy and Cell Biology, McGill University, Montreal, QC, Canada.
³ NeuroPoly Lab, Institute of Biomedical Engineering, Department of Computer Engineering and Software Engineering, École Polytechnique de Montréal, Montreal, QC, Canada.
⁴ Pediatric Storage Disorders Laboratory (PSDL), Departments of Pediatrics, Genetics and Neurology, Washington University School of Medicine, St. Louis, MO, United States.
⁵ Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, Canada.

Abstract

Introduction: Chronic 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 Hgsnat^P304L and post-mortem brain samples of MPS III patients.

Methods: Brain and spinal cord tissues of human MPS III patients, 6-month-old Hgsnat^P304L 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.

Results: Analyses 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.

Discussion: Our 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.

Keywords: GM3 ganglioside; diffusion basis spectrum imaging; lysosomal storage; mucopolysaccharidosis; myelination; oligodendrocyte.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work has been partially supported by operating grants PJT-156345 and PJT-180546 from the Canadian Institutes of Health Research and a research grant ND-1 from the Canadian Glycomics Network to AVP and GL, Elisa Linton Research Chair in Lysosomal Diseases and gifts from Cure Sanfilippo Foundation and Sanfilippo Children’s Foundation (Australia) to AVP and GL was supported by a salary award from FRQ-S.