Getting the upper hand in ALS.
Getting the upper hand in ALS.
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DOI：
10.1038/s41434-022-00314-9
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发表时间：
2022-04
期刊：
影响因子：
5.1
通讯作者：
中科院分区：
文献类型：
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作者：
泛素可能是描述最恰当的分子了——它在全身组织中无处不在。多泛素（polybiquitin）标记蛋白的多拷贝降解，这在各种神经退行性疾病中起重要作用。这一发现获得了诺贝尔奖，并成为研究和药物发现的关键领域。Genc等人提供了强有力的证据，表明uchl1——一种在多个水平上调节多泛素化蛋白的关键酶——可能能够逆转肌萎缩侧索硬化症（ALS）中上运动神经元的退化，ALS是最具侵袭性的神经退行性疾病之一。1869年Charcot对ALS的定义是，上肢和下肢运动神经元的丧失导致随意肌瘫痪，持续时间为3-5年。虽然约10%的ALS病例与C9orf72、TDP-43和SOD1等特定基因突变有关，但大多数是“散发性”的，没有已知的遗传来源。ALS现在也被认为是一种以TDP-43为中心的蛋白质病。Genc等人首先评估了UCHL1基因敲除小鼠，这些小鼠表现出明显的上运动神经元退行性变，其特征是沿其顶端树突[1]的脊椎严重丢失。在皮质脊髓束注射AAV-UCHL1导致上运动神经元逆行表达，并完全逆转这种形态退行性表型。虽然这证明了基因替代技术方法的概念，但可以预期的是，被敲除的基因的功能只是被取代了。更令人感兴趣的是，他们在小鼠模型的上运动神经元中应用了同样的UCHL1过表达，以治疗涉及TDP-43和SOD1突变的两种不同的ALS病因。值得注意的是，他们发现了非常相似的上运动神经元表型完全恢复。UCHL1的表达也导致错误折叠的SOD1和TDP-43蛋白积累水平降低。这表明通过一系列导致ALS的突变，UCHL1活性对神经元健康有更广泛的影响。由于散发性ALS没有已知的致病基因，因此无法用UCHL1建立遗传小鼠模型并进行测试。但是，结论当然是，在散发性ALS病例中增加UCHL1活性也可能有有益的影响。虽然ALS领域主要集中在下运动神经元，但这里主要关注的是上运动神经元。许多病理研究和一些临床研究表明，ALS早期的上运动神经元受累的迹象表明，这些神经元是过度活跃的。我们对这一领域也很感兴趣，并在大鼠模型中证明，AAV-9仅在运动皮层中敲低突变SOD1足以延迟疾病发作并延长寿命
Ubiquitin is perhaps the most aptly described molecule—ubiquitous to tissues throughout the body. Multiple copies of ubiquitin (polyubiquitin) tag proteins for degradation and this plays an important role in various neurodegenerative diseases. This discovery earned a Nobel prize and has become a critical area of research and drug discovery. Genc et al. provide strong evidence that UCHL1—an enzyme crucial for regulating polyubiquinated proteins at multiple levels—may be able to reverse degeneration of upper motor neurons in amyotrophic lateral sclerosis (ALS), one of the most aggressive neurodegenerative diseases. ALS, defined by Charcot in 1869, has to involve the loss of both upper and lower motor neurons leading to paralysis of voluntary muscles over a period of 3–5 years. While~ 10% of all ALS cases are associated with specific gene mutations involving C9orf72, TDP-43 and SOD1 and others, the majority are “sporadic” with no known genetic origin. ALS is also now considered a proteinopathy with TDP-43 as the central player. Genc et al. first assessed UCHL1 knockout mice, which showed significant degeneration of the upper motor neurons, characterized by severe loss of spines along their apical dendrites [1]. Injections of AAV-UCHL1 in the corticospinal tract led to retrograde expression in the upper motor neurons and complete reversal of this morphological degenerative phenotype. While this is proof of concept of a technical approach to gene replacement, it would be expected as the function of the knocked out gene is simply being replaced. Of greater interest is when they applied the same over-expression of UCHL1 specifically in the upper motor neurons of mouse models for two distinct causes of ALS that involve mutations in TDP-43 and SOD1. Remarkably, they found very similar complete restoration of the upper motor neuron phenotype. UCHL1 expression also led to reduced levels of misfolded SOD1 and TDP-43 protein accumulation. This suggests a wider influence of UCHL1 activity on neuronal health across a range of mutations that cause ALS. With no known causal gene for sporadic ALS, genetic mouse models cannot be developed and tested with UCHL1. But, the inference is of course that increasing UCHL1 activity in sporadic ALS cases may also have beneficial effects.While the ALS field has primarily concentrated on the lower motor neuron, of major interest here is the focus on the upper motor neuron. Signs of upper motor neuron involvement early in ALS comes from a number of pathological studies and some clinical studies showing that these neurons are hyperactive [2]. We have also been interested in this area and demonstrated that AAV-9 knockdown of mutant SOD1 only in the motor cortex was sufficient to delay disease onset and extend lifespan in a rat model
影响因子：
5.2
作者：
Thomsen, Gretchen M.;Avalos, Pablo;Svendsen, Clive N.
通讯作者：
Svendsen, Clive N.
影响因子：
5.3
作者：
Thomsen, Gretchen M.;Gowing, Genevieve;Svendsen, Clive N.
通讯作者：
Svendsen, Clive N.