A survival factor for axons: roles in disease and downstream mechanism

我们的神经系统没有轴突就不能工作，长轴突？电线将电信号从一个神经细胞（神经元）传导到另一个神经细胞。即使神经元的其他部分（细胞体和树突）存活下来，没有轴突的神经元在功能上也是死亡的。轴突是非常脆弱的，因为它们的巨大长度（高达一米的人）和他们需要提供必要的组成部分从细胞体的所有位置沿着他们的长度使用一个复杂的过程被称为？轴突运输？因此，轴突变性对许多神经退行性疾病的症状做出了重要贡献，包括多发性硬化症、青光眼、糖尿病性神经病、运动神经元疾病和阿尔茨海默病。的疾病。一旦失去，我们大脑和脊髓中的轴突就不能再生，因此在衰老和疾病中保护它们是至关重要的。我们最近确定了一种酶（Nmnat2）作为轴突生存因子使用神经元培养系统。我们提出，未能提供Nmnat2可能是负责轴突运输失败的疾病中的轴突死亡。这是基于实验，其中用一种类似但更持久的名为WldS的酶替代增加轴突存活并减轻疾病。WldS不存在于人类中，而Nmnat2存在，这使得这一新的发展特别令人兴奋。因为我们现在可以通过操纵人类拥有的单个分子来调节退化过程，我们可以在理解这种类型的退化方面取得快速进展，并找到阻止它的最佳方法。为了获得全面的了解，我们还需要在哺乳动物神经系统及其在神经退行性疾病中的作用的背景下研究这一过程。我们将对小鼠进行基因改造，以阻断或减少神经元中Nmnat 2的产生。当它的生产完全停止时，我们预计轴突将通过一种称为？沃勒样变性？我们已经研究了很多年的一种途径，可以使用WldS基因进行测试。当提议的生存因子的产生减少约50%时，我们预计轴突最初可能会存活，但变得更容易受到其他压力的影响，如神经毒素，物理压力，遗传缺陷？堵塞了吗我们的轴突甚至可能是正常的衰老通过测试轴突运输障碍中轴突Nmnat2水平是否降低，以及降低的程度是否与疾病的严重程度相关，我们的目标是了解导致轴突变性的分子步骤，并最终将其作为治疗目标。

Our nervous system cannot function without axons, the long ?wires? conducting electrical signals from one nerve cell (neuron) to another. Even if other parts of the neuron (the cell body and dendrites) survive, a neuron without an axon is functionally dead. Axons are very vulnerable because of their immense length (up to one metre in man) and their need to deliver essential components from cell bodies to all locations along their lengths using a sophisticated process known as ?axonal transport?. Consequently, axon degeneration makes critical contributions to symptoms in many neurodegenerative conditions, including multiple sclerosis, glaucoma, diabetic neuropathy, motor neuron disease and Alzheimer?s disease. Once lost, axons in our brain and spinal cord do not regenerate so it is essential to preserve them in ageing and disease. We recently identified an enzyme (Nmnat2) as an axon survival factor using a neuronal culture system. We propose that failure to deliver Nmnat2 could be responsible for axon death in diseases where axonal transport fails. This is based on experiments where substituting with a similar but longer-lasting enzyme named WldS increases axon survival and alleviates disease. WldS is not present in people whereas Nmnat2 is, which makes this new development particularly exciting. Because we can now regulate the degenerative process by manipulating a single molecule that humans do have, we can make rapid progress in understanding this type of degeneration and working out the best way to block it pharmacologically. To get the full picture, we also need to study this process in the context of a mammalian nervous system and its roles in neurodegenerative disorders. We will genetically modify mice to block or reduce the production of Nmnat2 in neurons. When its production stops altogether we expect that axons will die through a mechanism called ?Wallerian-like degeneration?, a pathway we have studied for many years and can test for using the WldS gene. When production of the proposed survival factor is reduced by around 50%, we expect that axons may initially survive but become more susceptible to other stresses such as neurotoxins, physical pressure, inherited defects that ?clog up? our axons and possibly even normal ageing. By testing whether axonal Nmnat2 levels are reduced in axonal transport disorders, and whether the degree of reduction is related to the severity of the disease, we aim to understand the molecular steps leading to axon degeneration and ultimately target them therapeutically.