title: Mechanism of abnormal growth in astrocytes derived from a mouse model of GM2 gangliosidosis.
abstract: Sandhoff disease is a progressive neurodegenerative disorder caused by mutations in the HEXB gene which encodes the beta-subunit of N-acetyl-beta-hexosaminidase A and B, resulting in the accumulation of the ganglioside GM2. We isolated astrocytes from the neonatal brain of Sandhoff disease model mice in which the N-acetyl-beta-hexosaminidase beta-subunit gene is genetically disrupted (ASD). Glycolipid profiles revealed that GM2/GA2 accumulated in the lysosomes and not on the cell surface of ASD astrocytes. In addition, GM3 was increased on the cell surface. We found remarkable differences in the cell proliferation of ASD astrocytes when compared with cells isolated from wild-type mice, with a faster growth rate of ASD cells. In addition, we observed increased extracellular, signal-regulated kinase (ERK) phosphorylation in ASD cells, but Akt phosphorylation was decreased. Furthermore, the phosphorylation of ERK in ASD cells was not dependent upon extracellular growth factors. Treatment of ASD astrocytes with recombinant N-acetyl-beta-hexosaminidase A resulted in a decrease of their growth rate and ERK phosphorylation. These results indicated that the up-regulation of ERK phosphorylation and the increase in proliferation of ASD astrocytes were dependent upon GM2/GA2 accumulation. These findings may represent a mechanism in linking the nerve cell death and reactive gliosis observed in Sandhoff disease.
authors.affiliation: Health Technology Research Center, National Institute of Advanced Industrial Science and Technology, Takamatsu, Kagawa, Japan.
authors.forename: Nagako
authors.initials: N
authors.lastname: Kawashima
authors.forename: Daisuke
authors.initials: D
authors.lastname: Tsuji
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Okuda
authors.forename: Kohji
authors.initials: K
authors.lastname: Itoh
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Nakayama
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000502:physiology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005434:Flow Cytometry / Q000379:methods; D005732:Gangliosides / Q000378:metabolism; D020143:Gangliosidoses, GM2 / Q000235:genetics / Q000378:metabolism*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D054818:Hexosaminidase A / Q000494:pharmacology; D054819:Hexosaminidase B / Q000235:genetics; D037102:Lectins / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019081:O Antigens / Q000378:metabolism; D012497:Sandhoff Disease / Q000235:genetics / Q000473:pathology*; D015398:Signal Transduction / Q000187:drug effects; D013116:Spinal Cord / Q000166:cytology
chemical_list: D005732:Gangliosides; D005904:Glial Fibrillary Acidic Protein; D037102:Lectins; D019081:O Antigens; C062875:ganglioside A2B5; D048049:Extracellular Signal-Regulated MAP Kinases; D054818:Hexosaminidase A; D054819:Hexosaminidase B