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- Title
Metabolic correction in microglia derived from Sandhoff disease model mice.
- Authors
Tsuji, Daisuke; Kuroki, Aya; Ishibashi, Yasuhiro; Itakura, Tomohiro; Itoh, Kohji
- Abstract
Sandhoff disease is an autosomal recessive lysosomal storage disease caused by a defect of the β-subunit gene ( HEXB) associated with simultaneous deficiencies of β-hexosaminidase A (HexA; αβ) and B (HexB; ββ), and excessive accumulation of GM2 ganglioside (GM2) and oligosaccharides with N-acetylglucosamine (GlcNAc) residues at their non-reducing termini. Recent studies have shown the involvement of microglial activation in neuroinflammation and neurodegeneration of this disease. We isolated primary microglial cells from the neonatal brains of Sandhoff disease model mice (SD mice) produced by disruption of the murine Hex β-subunit gene allele ( Hexb–/–). The cells expressed microglial cell-specific ionized calcium binding adaptor molecule 1 (Iba1)-immunoreactivity (IR) and antigen recognized by Ricinus communis agglutinin lectin-120 (RCA120), but not glial fibrillary acidic protein (GFAP)-IR specific for astrocytes. They also demonstrated significant intracellular accumulation of GM2 and GlcNAc-oligosaccharides. We produced a lentiviral vector encoding for the murine Hex β-subunit and transduced it into the microglia from SD mice with the recombinant lentivirus, causing elimination of the intracellularly accumulated GM2 and GlcNAc-oligosaccharides and secretion of Hex isozyme activities from the transduced SD microglial cells. Recomibinant HexA isozyme isolated from the conditioned medium of a Chinese hamster ovary (CHO) cell line simultaneously expressing the human HEXA (α-subunit) and HEXB genes was also found to be incorporated into the SD microglia via cell surface cation-independent mannose 6-phosphate receptor and mannose receptor to degrade the intracellularly accumulated GM2 and GlcNAc-oligosaccharides. These results suggest the therapeutic potential of recombinant lentivirus encoding the murine Hex β-subunit and the human HexA isozyme (αβ heterodimer) for metabolic cross-correction in microglial cells involved in progressive neurodegeneration in SD mice.
- Subjects
MICROGLIA; LYSOSOMAL storage diseases; ANIMAL models in research; INBORN errors of metabolism; NEURODEGENERATION; MICE
- Publication
Journal of Neurochemistry, 2005, Vol 94, Issue 6, p1631
- ISSN
0022-3042
- Publication type
Article
- DOI
10.1111/j.1471-4159.2005.03317.x