title: Specific induction of macrophage inflammatory protein 1-alpha in glial cells of Sandhoff disease model mice associated with accumulation of N-acetylhexosaminyl glycoconjugates.
abstract: Sandhoff disease is a lysosomal storage disease caused by simultaneous deficiencies of beta-hexosaminidase A (HexA; alphabeta) and B (HexB; betabeta), due to a primary defect of the beta-subunit gene (HEXB) associated with excessive accumulation of GM2 ganglioside (GM2) and oligosaccharides with N-acetylhexosamine residues at their non-reducing termini, and with neurosomatic manifestations. To elucidate the neuroinflammatory mechanisms involved in its pathogenesis, we analyzed the expression of chemokines in Sandhoff disease model mice (SD mice) produced by disruption of the murine Hex beta-subunit gene allele (Hexb-/-). We demonstrated that chemokine macrophage inflammatory protein-1 alpha (MIP-1alpha) was induced in brain regions, including the cerebral cortex, brain stem and cerebellum, of SD mice from an early stage of the pathogenesis but not in other systemic organs. On the other hand, little changes in other chemokine mRNAs, including those of RANTES (regulated upon activation, normal T expressed and secreted), MCP-1 (monocyte chemotactic protein-1), SLC (secondary lymphoid-tissue chemokine), fractalkine and SDF-1 (stromal derived factor-1), were detected. Significant up-regulation of MIP-1alpha mRNA and protein in the above-mentioned brain regions was observed in parallel with the accumulation of natural substrates of HexA and HexB. Immunohistochemical analysis revealed that MIP-1alpha-immunoreactivity (IR) in the above-mentioned brain regions of SD mice was co-localized in Iba1-IR-positive microglial cells and partly in glial fibrillary acidic protein (GFAP)-IR-positive astrocytes, in which marked accumulation of N-acetylglucosaminyl (GlcNAc)-oligosaccharides was observed from the presymptomatic stage of the disease. In contrast, little MIP-1alpha-IR was observed in neurons in which GM2 accumulated predominantly. These results suggest that specific induction of MIP-1alpha might coincide with the accumulation of GlcNAc-oligosaccharides due to a HexB deficiency in resident microglia and astrocytes in the brains of SD mice causing their activation and acceleration of the progressive neurodegeneration in SD mice.
authors.affiliation: Department of Medicinal Biotechnology, Institute of Medicinal Resources, Graduate School of Pharmaceutical Sciences, The University of Tokushima, 1-78 Sho-machi, Tokushima 770-8505, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Tsuji
authors.forename: Aya
authors.initials: A
authors.lastname: Kuroki
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Ishibashi
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Itakura
authors.forename: Jun
authors.initials: J
authors.lastname: Kuwahara
authors.forename: Shoji
authors.initials: S
authors.lastname: Yamanaka
authors.forename: Kohji
authors.initials: K
authors.lastname: Itoh
mesh_terms: D000117:Acetylglucosamine / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D002135:Calcium-Binding Proteins / Q000378:metabolism; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018925:Chemokines / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D005678:G(M2) Ganglioside / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006001:Glycoconjugates / Q000378:metabolism*; D054818:Hexosaminidase A; D054819:Hexosaminidase B; D019402:Macrophage Inflammatory Proteins / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008840:Microfilament Proteins; D017628:Microglia / Q000378:metabolism; D009457:Neuroglia / Q000378:metabolism* / Q000473:pathology; D021122:Protein Subunits / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D012497:Sandhoff Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015854:Up-Regulation / Q000502:physiology; D001619:beta-N-Acetylhexosaminidases / Q000172:deficiency / Q000235:genetics*
chemical_list: C491049:Aif1 protein, mouse; D002135:Calcium-Binding Proteins; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018925:Chemokines; D005904:Glial Fibrillary Acidic Protein; D006001:Glycoconjugates; D019402:Macrophage Inflammatory Proteins; D008840:Microfilament Proteins; D021122:Protein Subunits; D012333:RNA, Messenger; D005678:G(M2) Ganglioside; D054818:Hexosaminidase A; D054819:Hexosaminidase B; D001619:beta-N-Acetylhexosaminidases; D000117:Acetylglucosamine