Large-scale Analyses of CAV1 and CAV2 Suggest Their Expression is Higher in Post-mortem ALS Brain Tissue and Affects Survival
Large-scale Analyses of CAV1 and CAV2 Suggest Their Expression is Higher in Post-mortem ALS Brain Tissue and Affects Survival
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CAV1 和 CAV2 的大规模分析表明它们在 ALS 死后脑组织中表达较高并影响生存
DOI：
10.1101/2022.11.04.22281798
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发表时间：
2022
期刊：
影响因子：
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通讯作者：
Adey B
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作者：
Adey B
Caveolin-1和Caveolin-2（CAV 1和CAV 2）是与细胞间神经营养信号相关的蛋白质。有证据表明，CAV 1和CAV 2（CAV 1/2）基因在肌萎缩侧索硬化症（ALS）中发挥作用。疾病相关的变异已被确定在CAV 1/2增强子，减少基因表达，并导致破坏膜脂rafts.Methods：使用大型ALS全基因组测序和死后RNA测序数据集（5，987和365个组织样本，分别），和iPSC衍生的运动神经元从55个人，我们调查了CAV 1/2表达和增强子变体的ALS phenotype.Results的作用：我们报告了ALS病例和对照组之间的差异表达分析CAV 1和CAV 2基因在各种死后脑组织和三个独立的数据集。与对照组相比，ALS患者的CAV 1和CAV 2表达始终较高，在初级运动皮层、外侧运动皮层和小脑中具有显著结果。我们还发现，与MinE项目中的非携带者相比，CAV 1/2增强子突变携带者的生存率增加，并且ALSFRS测量的进展较慢。携带者的平均生存期增加了345天。讨论：这些结果增加了越来越多的证据将CAV 1和CAV 2基因与ALS联系起来。我们建议，携带CAV 1/2增强子突变的患者可以被概念化为ALS亚型，其表现为不太严重的ALS表型，具有较长的生存期和较慢的进展。ALS病例中CAV 1/2基因的上调可能指示因果通路或代偿机制。鉴于先前的研究支持CAV 1/2表达在ALS患者中的有益作用，我们认为这是一种补偿机制，以更好地适应现有的证据，尽管需要进一步研究与CAV 1/2相关的生物学途径来支持这一结论。
Introduction:Caveolin-1 and Caveolin-2 (CAV1 and CAV2) are proteins associated with intercellular neurotrophic signalling. There is converging evidence that CAV1 and CAV2 (CAV1/2) genes have a role in amyotrophic lateral sclerosis (ALS). Disease-associated variants have been identified within CAV1/2 enhancers, which reduce gene expression and lead to disruption of membrane lipid rafts.Methods:Using large ALS whole-genome sequencing and post-mortem RNA sequencing datasets (5,987 and 365 tissue samples, respectively), and iPSC-derived motor neurons from 55 individuals, we investigated the role of CAV1/2 expression and enhancer variants in the ALS phenotype.Results:We report a differential expression analysis between ALS cases and controls for CAV1 and CAV2 genes across various post-mortem brain tissues and three independent datasets. CAV1 and CAV2 expression was consistently higher in ALS patients compared to controls, with significant results across the primary motor cortex, lateral motor cortex, and cerebellum. We also identify increased survival among carriers of CAV1/2 enhancer mutations compared to non-carriers within Project MinE and slower progression as measured by the ALSFRS. Carriers showed a median increase in survival of 345 days.Discussion:These results add to an increasing body of evidence linking CAV1 and CAV2 genes to ALS. We propose that carriers of CAV1/2 enhancer mutations may be conceptualised as an ALS subtype who present a less severe ALS phenotype with a longer survival duration and slower progression. Upregulation of CAV1/2 genes in ALS cases may indicate a causal pathway or a compensatory mechanism. Given prior research supporting the beneficial role of CAV1/2 expression in ALS patients, we consider a compensatory mechanism to better fit the available evidence, although further investigation into the biological pathways associated with CAV1/2 is needed to support this conclusion.