Article

Mechanism of abnormal growth in astrocytes derived from a mouse model of GM2 gangliosidosis.

Health Technology Research Center, National Institute of Advanced Industrial Science and Technology, Takamatsu, Kagawa, Japan.
Journal of Neurochemistry (impact factor: 4.06). 09/2009; 111(4):1031-41. DOI:10.1111/j.1471-4159.2009.06391.x pp.1031-41
Source: PubMed

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.

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Keywords

ASD astrocytes
 
cell surface
 
ERK phosphorylation
 
extracellular growth factors
 
ganglioside GM2
 
Glycolipid profiles
 
GM2/GA2 accumulation
 
growth rate
 
HEXB gene
 
lysosomes
 
N-acetyl-beta-hexosaminidase
 
N-acetyl-beta-hexosaminidase beta-subunit gene
 
neonatal brain
 
nerve cell death
 
progressive neurodegenerative disorder
 
recombinant N-acetyl-beta-hexosaminidase
 
Sandhoff disease
 
Sandhoff disease model mice
 
signal-regulated kinase
 
wild-type mice
 

Nagako Kawashima