Neuroaxonal Dystrophy in Calcium-Independent Phospholipase A2β Deficiency Results from Insufficient Remodeling and Degeneration of Mitochondrial and Presynaptic Membranes
Neuroaxonal Dystrophy in Calcium-Independent Phospholipase A2β Deficiency Results from Insufficient Remodeling and Degeneration of Mitochondrial and Presynaptic Membranes
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DOI：
10.1523/jneurosci.0345-11.2011
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发表时间：
2011-08-03
影响因子：
5.3
通讯作者：
Sumi-Akamaru, Hisae
中科院分区：
文献类型：
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作者：
Beck, Goichi;Sugiura, Yuki;Sumi-Akamaru, Hisae
婴儿神经轴索营养不良（INAD）是一种致命的神经退行性疾病，其特征是CNS和PNS中广泛存在轴突轴突（球状体），由PLA 2G 6 [钙非依赖性磷脂酶A（2）β（iPLA（2）β）]的基因异常引起，该基因对膜磷脂的重塑至关重要。为了阐明INAD的病理机制，我们对iPLA（2）β基因敲除（KO）小鼠（INAD模型）的脊髓和坐骨神经进行了病理学分析。在15周（临床前阶段），经常观察到高碘酸希夫（PAS）阳性颗粒在近端轴突和大神经元的核周空间，这些都是强阳性的线粒体外膜的标记和内膜的标记阴性。到100周（临床晚期），PAS阳性颗粒和球状体在轴突的远端部分显著增加，超微结构检查显示，这些颗粒实际上是具有退化内膜的线粒体。轴突中线粒体的崩溃伴随着细胞骨架的局灶性消失。轴突终末的部分膜丢失也很明显，伴随着相同区域的膜变性。成像质谱显示灰质中含二十二碳六烯酸的磷脂酰胆碱显著增加，表明iPLA（2）β缺乏时膜重塑不足。在神经轴索营养不良中，突出的轴索变性可能由轴索运输后异常线粒体的崩溃来解释。线粒体内膜和突触前膜的重塑不足和变性似乎是iPLA（2）β-KO小鼠神经轴突营养不良的原因。
Infantile neuroaxonal dystrophy (INAD) is a fatal neurodegenerative disease characterized by the widespread presence of axonal swellings (spheroids) in the CNS and PNS and is caused by gene abnormality in PLA2G6 [ calcium-independent phospholipase A(2)beta (iPLA(2)beta)], which is essential for remodeling of membrane phospholipids. To clarify the pathomechanism of INAD, we pathologically analyzed the spinal cords and sciatic nerves of iPLA(2)beta knock-out (KO) mice, a model of INAD. At 15 weeks (preclinical stage), periodic acid-Schiff (PAS)-positive granules were frequently observed in proximal axons and the perinuclear space of large neurons, and these were strongly positive for a marker of the mitochondrial outer membrane and negative for a marker of the inner membrane. By 100 weeks (late clinical stage), PAS-positive granules and spheroids had increased significantly in the distal parts of axons, and ultrastructural examination revealed that these granules were, in fact, mitochondria with degenerative inner membranes. Collapse of mitochondria in axons was accompanied by focal disappearance of the cytoskeleton. Partial membrane loss at axon terminals was also evident, accompanied by degenerative membranes in the same areas. Imaging mass spectrometry showed a prominent increase of docosahexaenoic acid-containing phosphatidylcholine in the gray matter, suggesting insufficient membrane remodeling in the presence of iPLA(2)beta deficiency. Prominent axonal degeneration in neuroaxonal dystrophy might be explained by the collapse of abnormal mitochondria after axonal transportation. Insufficient remodeling and degeneration of mitochondrial inner membranes and presynaptic membranes appear to be the cause of the neuroaxonal dystrophy in iPLA(2)beta-KO mice.