Custer Sara K, Garden Gwenn A, Gill Nishi, Rueb Udo, Libby Randell T, Schultz Christian, Guyenet Stephan J, Deller Thomas, Westrum Lesnick E, Sopher Bryce L, La Spada Albert R
Department of Laboratory Medicine, University of Washington Medical Center, Seattle, Washington 98195, USA.
Nat Neurosci. 2006 Oct;9(10):1302-11. doi: 10.1038/nn1750. Epub 2006 Aug 27.
Non-neuronal cells may be pivotal in neurodegenerative disease, but the mechanistic basis of this effect remains ill-defined. In the polyglutamine disease spinocerebellar ataxia type 7 (SCA7), Purkinje cells undergo non-cell-autonomous degeneration in transgenic mice. We considered the possibility that glial dysfunction leads to Purkinje cell degeneration, and generated mice that express ataxin-7 in Bergmann glia of the cerebellum with the Gfa2 promoter. Bergmann glia-specific expression of mutant ataxin-7 was sufficient to produce ataxia and neurodegeneration. Expression of the Bergmann glia-specific glutamate transporter GLAST was reduced in Gfa2-SCA7 mice and was associated with impaired glutamate transport in cultured Bergmann glia, cerebellar slices and cerebellar synaptosomes. Ultrastructural analysis of Purkinje cells revealed findings of dark cell degeneration consistent with excitotoxic injury. Our studies indicate that impairment of glutamate transport secondary to glial dysfunction contributes to SCA7 neurodegeneration, and suggest a similar role for glial dysfunction in other polyglutamine diseases and SCAs.
非神经元细胞可能在神经退行性疾病中起关键作用，但其作用机制仍不明确。在多聚谷氨酰胺疾病脊髓小脑共济失调7型（SCA7）中，转基因小鼠的浦肯野细胞会发生非细胞自主性变性。我们考虑了神经胶质功能障碍导致浦肯野细胞变性的可能性，并利用Gfa2启动子培育出在小脑伯格曼神经胶质细胞中表达ataxin-7的小鼠。突变型ataxin-7在伯格曼神经胶质细胞中的特异性表达足以导致共济失调和神经变性。在Gfa2-SCA7小鼠中，伯格曼神经胶质细胞特异性谷氨酸转运体GLAST的表达降低，并且与培养的伯格曼神经胶质细胞、小脑切片和小脑突触体中的谷氨酸转运受损有关。对浦肯野细胞的超微结构分析揭示了与兴奋性毒性损伤一致的暗细胞变性结果。我们的研究表明，神经胶质功能障碍继发的谷氨酸转运受损促成了SCA7神经变性，并提示神经胶质功能障碍在其他多聚谷氨酰胺疾病和脊髓小脑共济失调中也起类似作用。
