title: FcRγ-dependent immune activation initiates astrogliosis during the asymptomatic phase of Sandhoff disease model mice.
abstract: Sandhoff disease (SD) is caused by the loss of β-hexosaminidase (Hex) enzymatic activity in lysosomes resulting from Hexb mutations. In SD patients, the Hex substrate GM2 ganglioside accumulates abnormally in neuronal cells, resulting in neuronal loss, microglial activation, and astrogliosis. Hexb-/-mice, which manifest a phenotype similar to SD, serve as animal models for examining the pathophysiology of SD. Hexb-/-mice reach ~8 weeks without obvious neurological defects; however, trembling begins at 12 weeks and is accompanied by startle reactions and increased limb tone. These symptoms gradually become severe by 16-18 weeks. Immune reactions caused by autoantibodies have been recently associated with the pathology of SD. The inhibition of immune activation may represent a novel therapeutic target for SD. Herein, SD mice (Hexb-/-) were crossed to mice lacking an activating immune receptor (FcRγ-/-) to elucidate the potential relationship between immune responses activated through SD autoantibodies and astrogliosis. Microglial activation and astrogliosis were observed in cortices of Hexb-/-mice during the asymptomatic phase, and were inhibited in Hexb-/-FcRγ-/-mice. Moreover, early astrogliosis and impaired motor coordination in Hexb-/-mice could be ameliorated by immunosuppressants, such as FTY720. Our findings demonstrate the importance of early treatment and the therapeutic effectiveness of immunosuppression in SD.
authors.affiliation: Department of Pharmacology, Meiji Pharmaceutical University, Tokyo, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Ogawa
authors.affiliation: Department of Pharmacology, Meiji Pharmaceutical University, Tokyo, Japan.
authors.forename: Takafumi
authors.initials: T
authors.lastname: Sano
authors.affiliation: Department of Pharmacology, Meiji Pharmaceutical University, Tokyo, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Irisa
authors.affiliation: Department of Functional Bioanalysis, Meiji Pharmaceutical University, Tokyo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kodama
authors.affiliation: Department of Pharmacology, Meiji Pharmaceutical University, Tokyo, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Saito
authors.affiliation: Department of Pharmacology, Meiji Pharmaceutical University, Tokyo, Japan.
authors.forename: Eiri
authors.initials: E
authors.lastname: Furusawa
authors.affiliation: Department of Pharmacology, Meiji Pharmaceutical University, Tokyo, Japan.
authors.forename: Katsutoshi
authors.initials: K
authors.lastname: Kaizu
authors.affiliation: Department of Pharmacology, Meiji Pharmaceutical University, Tokyo, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Yanagi
authors.affiliation: Department of Functional Bioanalysis, Meiji Pharmaceutical University, Tokyo, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Tsukimura
authors.affiliation: Department of Functional Bioanalysis, Meiji Pharmaceutical University, Tokyo, Japan.
authors.forename: Tadayasu
authors.initials: T
authors.lastname: Togawa
authors.affiliation: Department of Pathology, Yokohama City University School of Medicine, Yokohama, Japan.
authors.forename: Shoji
authors.initials: S
authors.lastname: Yamanaka
authors.affiliation: Department of Medicinal Biotechnology, Institute for Medicinal Research, Graduate School of Pharmaceutical Sciences, The University of Tokushima, Tokushima, Japan.
authors.forename: Kohji
authors.initials: K
authors.lastname: Itoh
authors.affiliation: Department of Clinical Genetics, Meiji Pharmaceutical University, Tokyo, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Sakuraba
authors.affiliation: Department of Pharmacology, Meiji Pharmaceutical University, Tokyo, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Oishi
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D002540:Cerebral Cortex / Q000473:pathology; D004195:Disease Models, Animal; D000068876:Fingolimod Hydrochloride / Q000494:pharmacology; D005678:G(M2) Ganglioside / Q000378:metabolism; D005911:Gliosis / Q000276:immunology* / Q000473:pathology*; D006579:Heterozygote; D007109:Immunity / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D010641:Phenotype; D011961:Receptors, Fc / Q000172:deficiency / Q000378:metabolism*; D012497:Sandhoff Disease / Q000276:immunology* / Q000473:pathology* / Q000503:physiopathology; D015854:Up-Regulation / Q000187:drug effects; D016138:Walking; D054821:beta-Hexosaminidase beta Chain / Q000378:metabolism
chemical_list: D007166:Immunosuppressive Agents; D011961:Receptors, Fc; D005678:G(M2) Ganglioside; D054821:beta-Hexosaminidase beta Chain; D000068876:Fingolimod Hydrochloride