Department of Cell and Regenerative Biology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, USA.
Proc Natl Acad Sci U S A. 2012 Mar 13;109(11):E656-64. doi: 10.1073/pnas.1110470109. Epub 2012 Feb 21.
To investigate the mechanistic basis for central nervous system (CNS) neurodegeneration in the disease ataxia-telangiectasia (A-T), we analyzed flies mutant for the causative gene A-T mutated (ATM). ATM encodes a protein kinase that functions to monitor the genomic integrity of cells and control cell cycle, DNA repair, and apoptosis programs. Mutation of the C-terminal amino acid in Drosophila ATM inhibited the kinase activity and caused neuron and glial cell death in the adult brain and a reduction in mobility and longevity. These data indicate that reduced ATM kinase activity is sufficient to cause neurodegeneration in A-T. ATM kinase mutant flies also had elevated expression of innate immune response genes in glial cells. ATM knockdown in glial cells, but not neurons, was sufficient to cause neuron and glial cell death, a reduction in mobility and longevity, and elevated expression of innate immune response genes in glial cells, indicating that a non-cell-autonomous mechanism contributes to neurodegeneration in A-T. Taken together, these data suggest that early-onset CNS neurodegeneration in A-T is similar to late-onset CNS neurodegeneration in diseases such as Alzheimer's in which uncontrolled inflammatory response mediated by glial cells drives neurodegeneration.
为了研究疾病共济失调毛细血管扩张症（A-T）中中枢神经系统（CNS）神经退行性变的机制基础，我们分析了突变体果蝇。该突变体果蝇的致病基因 A-T 突变（ATM）发生了突变。ATM 编码一种蛋白激酶，其功能是监测细胞的基因组完整性，并控制细胞周期、DNA 修复和细胞凋亡程序。在果蝇中，ATM 的 C 末端氨基酸的突变抑制了激酶活性，并导致成年大脑中的神经元和神经胶质细胞死亡，以及运动能力和寿命的降低。这些数据表明，降低 ATM 激酶活性足以导致 A-T 中的神经退行性变。ATM 激酶突变体果蝇的神经胶质细胞中还存在固有免疫反应基因的高表达。在神经胶质细胞而非神经元中敲低 ATM 足以导致神经元和神经胶质细胞死亡、运动能力和寿命降低以及神经胶质细胞中固有免疫反应基因的高表达，表明非细胞自主机制有助于 A-T 中的神经退行性变。总之，这些数据表明，A-T 中早发性 CNS 神经退行性变与阿尔茨海默病等疾病的晚发性 CNS 神经退行性变相似，其中由神经胶质细胞介导的不受控制的炎症反应驱动神经退行性变。
