UNC13A in amyotrophic lateral sclerosis: from genetic association to therapeutic target.
UNC13A in amyotrophic lateral sclerosis: from genetic association to therapeutic target.
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DOI：
10.1136/jnnp-2022-330504
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发表时间：
2023-08
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肌萎缩侧索硬化症（ALS）是一种致命的神经退行性疾病，治疗选择有限，病理生理学尚未完全了解。虽然全基因组关联研究（GWAS）已经推进了我们对疾病的理解，但风险多态性导致疾病发病机制的确切方式仍不清楚。相关的，GWAS已经表明UNC 13 A基因的多态性（rs 12608932）与ALS和额颞叶痴呆（FTD）的风险相关。rs 12608932处C等位基因的纯合性改变了ALS表型，因为这些患者更可能在基线时患有延髓发作性疾病、认知障碍和FTD，并且生存期更短。UNC 13 A在神经元组织中表达，并通过启动和对接突触囊泡参与维持突触活性区。在不存在功能性TDP-43的情况下，UNC 13 A中的风险变体导致在UNC 13 A信使RNA中包含隐蔽外显子，随后导致无义介导的衰变，伴随功能性蛋白质的丧失。UNC 13 A的消耗导致神经传递受损。最近的发现已经将UNC 13 A确定为ALS治疗开发的潜在靶点，目前正在进行UNC 13 A病例中使用碳酸锂的确证性试验，目前正在考虑使用反义寡核苷酸的未来方法。考虑到UNC 13 A是一种有效的表型修饰剂，它也可能影响临床试验结果。本综述描述了从最初发现UNC 13 A作为ALS风险基因到目前正在探索的治疗方案的路径，以及在未来的试验中如何考虑其独特表型的知识。
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with limited treatment options and an incompletely understood pathophysiology. Although genomewide association studies (GWAS) have advanced our understanding of the disease, the precise manner in which risk polymorphisms contribute to disease pathogenesis remains unclear. Of relevance, GWAS have shown that a polymorphism (rs12608932) in the UNC13A gene is associated with risk for both ALS and frontotemporal dementia (FTD). Homozygosity for the C-allele at rs12608932 modifies the ALS phenotype, as these patients are more likely to have bulbar-onset disease, cognitive impairment and FTD at baseline as well as shorter survival. UNC13A is expressed in neuronal tissue and is involved in maintaining synaptic active zones, by enabling the priming and docking of synaptic vesicles. In the absence of functional TDP-43, risk variants in UNC13A lead to the inclusion of a cryptic exon in UNC13A messenger RNA, subsequently leading to nonsense mediated decay, with loss of functional protein. Depletion of UNC13A leads to impaired neurotransmission. Recent discoveries have identified UNC13A as a potential target for therapy development in ALS, with a confirmatory trial with lithium carbonate in UNC13A cases now underway and future approaches with antisense oligonucleotides currently under consideration. Considering UNC13A is a potent phenotypic modifier, it may also impact clinical trial outcomes. This present review describes the path from the initial discovery of UNC13A as a risk gene in ALS to the current therapeutic options being explored and how knowledge of its distinct phenotype needs to be taken into account in future trials.
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影响因子：
4.8
作者：
Cooper-Knock J;Harvey C;Zhang S;Moll T;Timpanaro IS;Kenna KP;Iacoangeli A;Veldink JH
通讯作者：
Veldink JH
DOI：
10.1136/jnnp-2020-322983
发表时间：
2020-11-11
期刊：
Journal of neurology, neurosurgery, and psychiatry
影响因子：
--
作者：
de Boer EMJ;Orie VK;Williams T;Baker MR;De Oliveira HM;Polvikoski T;Silsby M;Menon P;van den Bos M;Halliday GM;van den Berg LH;Van Den Bosch L;van Damme P;Kiernan MC;van Es MA;Vucic S
通讯作者：
Vucic S
影响因子：
4.2
作者：
Chiò A;Mora G;Restagno G;Brunetti M;Ossola I;Barberis M;Ferrucci L;Canosa A;Manera U;Moglia C;Fuda G;Traynor BJ;Calvo A
通讯作者：
Calvo A
影响因子：
4.7
作者：
Dyer, Marcus S.;Reale, Laura A.;Blizzard, Catherine A.
通讯作者：
Blizzard, Catherine A.
影响因子：
16.6
作者：
Camacho M;Basu J;Trimbuch T;Chang S;Pulido-Lozano C;Chang SS;Duluvova I;Abo-Rady M;Rizo J;Rosenmund C
通讯作者：
Rosenmund C