Axonal dystrophy of dorsal root ganglion sensory neurons in a mouse model of Niemann–Pick disease type C
Axonal dystrophy of dorsal root ganglion sensory neurons in a mouse model of Niemann–Pick disease type C
复制标题
C 型尼曼-皮克病小鼠模型中背根神经节感觉神经元的轴突营养不良
DOI：
10.1016/j.expneurol.2004.03.002
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发表时间：
2004
影响因子：
5.3
通讯作者：
K. Ohno
中科院分区：
文献类型：
--
作者：
S. Ohara;Yoko Ukita;H. Ninomiya;K. Ohno
C型尼曼-匹克病（NP-C）是一种进行性和致死性神经系统疾病，其特征是细胞内胆固醇和糖脂的积聚。Balb/c-npc 1突变株是遗传上真实的NP-C鼠模型，纯合子小鼠显示进行性体重减轻和震颤或共济失调，直至12-14周龄死亡。在神经病理学上，已知该模型忠实地再现了NP-C的主要组织学特征，包括神经元储存、肿胀轴突（球状体）的出现和神经元损失，尽管神经变性的细胞机制在很大程度上是未知的。为了探讨NP-C感觉神经元的神经变性模式，我们在延髓背柱核和脊髓背角水平研究了背根神经节（DRG）神经元的中枢突起，特别注意突触前轴突终末的超微结构变化。对脊髓背柱核中轴突球体的出现和脊神经根中轴突的丢失进行定量评估。我们发现，薄核发展众多的轴突球体后，只有3周。在6周和9周，营养不良的轴突，这是从简单的轴突球体分开的超微结构存在的独特的管泡状元件，逐步增加的大小和数量。这些神经病理学表现与正常衰老小鼠的GAD相同。突触前元件专门参与球体的形成。楔状核和脊髓背角的轴突球体较少，只有罕见的营养不良的变化。这与9周龄时NP-C小鼠与对照组相比L4-5背根轴突数量的显著下降有关。这些结果支持存在的长度依赖性轴突病变的DRG神经元的中央过程中，并与改变轴突运输，这是在GAD的发病机制在生理老化，可能是一个潜在的机制在NP-C的神经元变性的观点是一致的。在临床上，GAD的过早发展可能是导致共济失调的原因，共济失调是这种疾病的早期表现之一。
Niemann–Pick disease type C (NP-C) is a progressive and fatal neurological disorder characterized by intracellular accumulation of cholesterol and glycolipid. A Balb/c-npc1 mutant strain is a genetically authentic murine model of NP-C, and homozygous mice show progressive weight loss and tremor or ataxia until death at 12–14 weeks of age. Neuropathologically, this model is known to faithfully reproduce the cardinal histologic features of NP-C including neuronal storage, appearance of swollen axons (spheroids), and neuronal loss, although the cellular mechanisms of neural degeneration are largely unknown. To investigate the mode of neural degeneration of sensory neurons in NP-C, we studied the central processes of dorsal root ganglion (DRG) neurons at the level of the medullary dorsal column nuclei and the spinal dorsal horn with special attention to the ultrastructural changes of presynaptic axon terminals. The appearance of axonal spheroids in the dorsal column nuclei and the loss of axons in the spinal nerve roots were assessed quantitatively. We show that the gracile nuclei develop numerous axonal spheroids after only 3 weeks. At 6 and 9 weeks, dystrophic axons, which were separated from simple axonal spheroids by the ultrastructural presence of distinctive tubulo-vesicular elements, progressively increased in size and number. These neuropathological findings are identical to those of gracile axonal dystrophy (GAD) of the normal aging mouse. Presynaptic elements were exclusively involved in spheroid formation. The cuneate nuclei and the spinal dorsal horn revealed fewer axonal spheroids and only rare dystrophic changes. This was associated with a significant drop in the number of L4–5 dorsal root axons in NP-C mouse at 9 weeks of age compared with controls. These results support the existence of a length-dependent axonopathy in the central processes of DRG neurons and are consistent with the view that altered axonal transport, which is implicated in the pathogenesis of GAD in physiological aging, may be an underlying mechanism in neuronal degeneration in NP-C. Clinically, the premature development of GAD may be responsible for ataxia, one of the early manifestations of this disease.
影响因子：
56.9
作者：
Davies, JP;Chen, FW;Ioannou, YA
通讯作者：
Ioannou, YA