Severe Central Nervous System Demyelination in Sanfilippo Disease

Abstract

Neurodegeneration and chronic progressive neuroinflammation are well-documented in neurological lysosomal storage diseases, including Sanfilippo disease or mucopolysaccharidosis III (MPS III). Since chronic neuroinflammation has been linked to white matter tract pathology and defects in axonal transmission, we analysed axonal myelination and white matter density in the mouse model of MPS IIIC and human post-mortem brain samples from MPS IIIA, C, and D patients. Analyses of corpus callosum (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. When brains of 7-month-old MPS IIIC mice were analysed by ex-vivo Diffusion Basis Spectrum Imaging to assess microarchitectural changes in the corpus callosum, we found compelling signs of demyelination (26% increase in radial diffusivity) and tissue loss (76% increase in hindered diffusivity). Our findings demonstrate an import role for white matter injury in the pathophysiology of MPS III. Moreover, this study reveals specific parameters and brain regions for MRI analysis, a crucial non-invasive method to evaluate disease progression and therapeutic response in neurological lysosomal storage diseases.

Heterologous HSPC transplantation rescues neuroinflammation and ameliorates peripheral manifestations in the mouse model of lysosomal transmembrane enzyme deficiency, MPS IIIC

“…According to our published data [40], at this age, pyramidal neurons of MPS IIIC mice already show synaptic deficits and significantly reduced density of dendritic spines. Similarly, levels of activated microglia show a drastic increase already at P25 [41]. Further studies are required to determine whether transplantation of mice at an earlier age would show efficacy in preventing CNS deficits, however, since most of MPS IIIC patients are diagnosed post-symptomatically, we believe that our experimental design reflects the current patient situation.…”

Multi-omics analyses of early-onset familial Alzheimer's disease and Sanfilippo syndrome zebrafish models reveal commonalities in disease mechanisms

“…Together, our results along with previous literature of animal models of MPS diseases support that changes to oligodendrocyte differentiation and/or function occur due to the excess mucopolysaccharides in symptomatic MPS disease stages. In children with MPS III, loss of myelin (132,133), and reduction of key oligodendrocyte proteins (128) has been observed. However, changes to oligodendrocyte function and myelination are not currently regarded as significant contributors to symptom manifestation.…”