Götz R, Karch C, Digby M R, Troppmair J, Rapp U R, Sendtner M
Klinische Forschergruppe Neuroregeneration, Department of Neurology University of Würzburg, Versbacher Strasse 5, D-97080 Würzburg, Germany.
Hum Mol Genet. 2000 Oct 12;9(17):2479-89. doi: 10.1093/hmg/9.17.2479.
The human neuronal apoptosis inhibitory protein (NAIP) gene has been discovered as a candidate gene for spinal muscular atrophy, a genetic disorder characterized by motor neuron loss in the spinal cord. The telomeric NAIP gene on human chromosome 5 is deleted together with survival motor neurons (SMN) in many cases of the most severe forms of the disorder. NAIP, c-IAP1 (inhibitor of apoptosis-1), c-IAP2, X-IAP, survivin and Apollon comprise the mammalian inhibitors of the apoptosis family and contain an N-terminal domain with 1-3 imperfect repeats of an approximately 65 amino acids domain named the baculovirus IAP repeat (BIR) motif. We identified six NAIP genes in the mouse genome which were found to be expressed in a broad range of tissues. Furthermore, we have investigated the effects of NAIP in the rat pheochromocytoma PC12 cell line. These cells differentiate in the presence of nerve growth factor (NGF) into cells that resemble sympathetic neurons. We observed that NAIP overexpression impaired NGF-induced neurite outgrowth. The BIR motifs of NAIP (residues 1-345) were not required for this effect. However, the BIR domains of NAIP were essential to prevent apoptosis in PC12 cells after NGF deprivation or TNF-alpha receptor stimulation. Expression of full-length but not BIR-deleted-NAIP protects against cell death. This correlates with reduced activity of the cell death effector protease, caspase-3, in lysates of NAIP-PC12 cells, as measured by cleavage of the fluorogenic tetrapeptide substrate Asp-Glu-Val-Asp. Thus, unregulation of cellular differentiation and/or caspase suppression may contribute to motoneuron dysfunction and cell death in spinal muscular atrophy where NAIP is mutated.
人类神经元凋亡抑制蛋白（NAIP）基因已被发现是脊髓性肌萎缩症的候选基因，脊髓性肌萎缩症是一种以脊髓运动神经元丧失为特征的遗传性疾病。在许多最严重形式的该疾病病例中，人类5号染色体上的端粒NAIP基因与生存运动神经元（SMN）一起缺失。NAIP、细胞凋亡抑制蛋白1（c-IAP1）、细胞凋亡抑制蛋白2（c-IAP2）、X连锁凋亡抑制蛋白（X-IAP）、生存素和阿波罗蛋白构成了哺乳动物凋亡抑制蛋白家族，它们都含有一个N端结构域，该结构域有1至3个约65个氨基酸的不完全重复序列，名为杆状病毒IAP重复序列（BIR）基序。我们在小鼠基因组中鉴定出六个NAIP基因，发现它们在广泛的组织中表达。此外，我们研究了NAIP对大鼠嗜铬细胞瘤PC12细胞系的影响。这些细胞在神经生长因子（NGF）存在的情况下分化为类似交感神经元的细胞。我们观察到NAIP过表达会损害NGF诱导的神经突生长。NAIP的BIR基序（第1至345位氨基酸）对这种作用并非必需。然而，NAIP的BIR结构域对于在NGF剥夺或肿瘤坏死因子-α受体刺激后防止PC12细胞凋亡至关重要。全长而非缺失BIR的NAIP的表达可保护细胞免于死亡。这与通过荧光四肽底物天冬氨酸-谷氨酸-缬氨酸-天冬氨酸的切割所测定的，NAIP-PC12细胞裂解物中细胞死亡效应蛋白酶半胱天冬酶-3活性降低相关。因此，细胞分化的失调和/或半胱天冬酶的抑制可能导致NAIP发生突变的脊髓性肌萎缩症中的运动神经元功能障碍和细胞死亡。
