Alterations of membrane lipids and in gene expression of ganglioside metabolism in different brain structures in a mouse model of mucopolysaccharidosis type I (MPS I)

Abstract

Mucopolysaccharidosis I (MPS I) is a congenital disorder caused by the deficiency of α-l-iduronidase (IDUA), with the accumulation of glycosaminoglycans (GAGs) in the CNS. Although GAG toxicity is not fully understood, previous works suggest a GAG-induced alteration in neuronal membrane composition. This study is aimed to evaluate the levels and distribution of gangliosides and cholesterol in different brain regions (cortex, cerebellum, hippocampus and hypothalamus) in a model using IDUA knockout (KO) mice (C57BL/6). Lipids were extracted with chloroform-methanol and then total gangliosides and cholesterol were determined, followed by ganglioside profile analyses. While no changes in cholesterol content were observed, the results showed a tissue dependent ganglioside alteration in KO mice: a total ganglioside increase in cortex and cerebellum, and a selective presence of GM3, GM2 and GD3 gangliosides in the hippocampus and hypothalamus. To elucidate this, we evaluated gene expression of ganglioside synthesis (GM3, GD3 and GM2/GD2 synthases) and degradation of (Neuraminidase1) enzymes in the cerebellum and hippocampus by RT-sq-PCR. The results obtained with KO mice showed a reduced expression of GD3 and GM2/GD2 synthases and Neuraminidase1 in cerebellum; and a decrease in GM2/GD2 synthase and Neuraminidase1 in the hippocampus. These data suggest that the observed ganglioside changes result from a combined effect of GAGs on ganglioside biosynthesis and degradation.

Subregional brain distribution of simple and complex glycosphingolipids in the mucopolysaccharidosis type I (Hurler syndrome) mouse: impact of diet

“…Both reduced neuraminidase activity together with reduced G D3 and G M2 /G M3 synthase activity were deemed responsible for the regional elevations in gangliosides in the HS brain (Kreutz et al . ). Our results support these findings of elevations in G M2 , G M3 and G D3 in the hippocampus, as well as a demonstrated elevation in G M1 in the cerebellum and cortex, noting a difference in the methodology, mass spectrometry used in this study being more specific and quantitative than thin layer chromatography (TLC) used by Kreutz et al .…”

“…Our results support these findings of elevations in G M2 , G M3 and G D3 in the hippocampus, as well as a demonstrated elevation in G M1 in the cerebellum and cortex, noting a difference in the methodology, mass spectrometry used in this study being more specific and quantitative than thin layer chromatography (TLC) used by Kreutz et al . (). The gangliosides were generally congruent between the brain stem, cortex, cerebellum, hippocampus and subcortex, with the 18:0 acyl species predominating in each class of ganglioside, consistent with the lipid profile of the brain.…”

Growth patterns for untreated individuals with MPS I: Report from the international MPS I registry

“…An initial report of a brain necropsy in MPS I identified swelling of most of the large cerebral cortical neurons with increased numbers of astrocytes, numerous perivascular aggregations of fibrous astrocytes throughout gray matter, and greatly enlarged perivascular spaces in the white matter filled with collagen and microglial phagocytes (Bishton, Norman, & Tingey, ). Brain assessments in MPS disorders also demonstrated a mesenchymal contribution to increased brain size that is due to mononuclear cells filled with GAGs in distended periadventitial spaces, GAG accumulation in leptomeninges, and, instead of GAGs, the neurons contained an excessive amount of glycolipid‐like material (Dekaban & Constantopoulos, ) shown to be an accumulation of sphingolipids (Constantopoulos & Dekaban, ; Kreutz et al, ). Brain MRIs of attenuated MPS I individuals demonstrate dilated perivascular spaces and enlargement of subarachnoid spaces in addition to increased size of supratentoral ventricles (Matheus et al, ).…”

Shedding Light on the Molecular Pathology of Amyloid Plaques in Transgenic Alzheimer’s Disease Mice Using Multimodal MALDI Imaging Mass Spectrometry

“…66 This in line with the reported accumulations of GM2 and GM3 in lysosomal storage disorders. 67,68 Phospholipids are essential constituents of neuronal membranes providing structural integrity and functional properties. 69 Moreover, lysophospholipids, metabolic intermediates of phospholipid metabolism 70 interact with the lipid and protein moieties of neural membranes and modulate the function of neural membrane proteins, such as enzymes and growth factors.…”