Sensory neuropathy attributable to loss of Bcl-w.
Sensory neuropathy attributable to loss of Bcl-w.
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DOI：
10.1523/jneurosci.3347-10.2011
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发表时间：
2011-02-02
期刊：
影响因子：
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通讯作者：
Segal RA
中科院分区：
文献类型：
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作者：
Courchesne SL;Karch C;Pazyra-Murphy MF;Segal RA
小纤维感觉神经病是一种常见的疾病，其中小直径伤害感受器的进行性变性导致对四肢中的热刺激和疼痛感觉的敏感性降低。在大多数患者中，小纤维感觉神经病变的原因尚不清楚，治疗选择有限。在这里，我们表明，Bcl-w（Bcl-2L 2）是所需的小纤维伤害性感觉神经元的活力。Bcl-w −/−小鼠表现出成年期开始的温度感觉进行性下降和表皮伤害感受器神经支配减少。这种去神经发生而没有细胞体损失，表明缺乏Bcl-w导致原发性轴突病。与这种表型相一致，我们表明，Bcl-w，在密切相关的Bcl-2和Bcl-xL相反，是丰富的感觉神经元的轴突和Bcl-w防止轴突的死亡。Bcl-w −/−感觉神经元表现出线粒体异常，包括轴突线粒体大小、轴突线粒体膜电位和细胞ATP水平的改变。总的来说，这些数据建立了bcl-w −/−小鼠作为小纤维感觉神经病的动物模型，并提供了关于bcl-w和线粒体在预防轴突变性中的作用的新见解。
Small fiber sensory neuropathy is a common disorder in which progressive degeneration of small diameter nociceptors causes decreased sensitivity to thermal stimuli and painful sensations in the extremities. In the majority of patients, the cause of small fiber sensory neuropathy is unknown, and treatment options are limited. Here, we show that Bcl-w (Bcl-2l2) is required for the viability of small fiber nociceptive sensory neurons. Bcl-w −/− mice demonstrate an adult-onset progressive decline in thermosensation and a decrease in nociceptor innervation of the epidermis. This denervation occurs without cell body loss, indicating that lack of Bcl-w results in a primary axonopathy. Consistent with this phenotype, we show that Bcl-w, in contrast to the closely related Bcl-2 and Bcl-xL, is enriched in axons of sensory neurons and that Bcl-w prevents the dying back of axons. Bcl-w −/− sensory neurons exhibit mitochondrial abnormalities, including alterations in axonal mitochondrial size, axonal mitochondrial membrane potential, and cellular ATP levels. Collectively, these data establish bcl-w −/− mice as an animal model of small fiber sensory neuropathy, and provide new insight regarding the role of bcl-w and of mitochondria in preventing axonal degeneration.