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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DOI：
10.3389/fncel.2023.1112405
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发表时间：
2023
影响因子：
5.3
通讯作者：
Iacoangeli, Alfredo
中科院分区：
文献类型：
--
作者：
Adey, Brett N.;Cooper-Knock, Johnathan;Al Khleifat, Ahmad;Fogh, Isabella;van Damme, Philip;Corcia, Philippe;Couratier, Philippe;Hardiman, Orla;McLaughlin, Russell;Gotkine, Marc;Drory, Vivian;Silani, Vincenzo;Ticozzi, Nicola;Veldink, Jan H.;van den Berg, Leonard H.;de Carvalho, Mamede;Pinto, Susana;Pardina, Jesus S. Mora S.;Panades, Monica Povedano;Andersen, Peter M.;Weber, Markus;Basak, Nazli A.;Shaw, Christopher E.;Shaw, Pamela J.;Morrison, Karen E.;Landers, John E.;Glass, Jonathan D.;Vourc'h, Patrick;Dobson, Richard J. B.;Breen, Gerome;Al-Chalabi, Ammar;Jones, Ashley R.;Iacoangeli, Alfredo
关键词：
Caveolin-1和Caveolin-2 （CAV1和CAV2）是细胞间神经营养信号传导相关的蛋白。越来越多的证据表明，CAV1和CAV2 （CAV1/2）基因在肌萎缩性侧索硬化症（ALS）中发挥作用。在CAV1/2增强子中已经发现了与疾病相关的变异体，其减少基因表达并导致膜脂筏的破坏。方法：利用大型ALS全基因组测序和死后RNA测序数据集（分别为5,987和365个组织样本），以及来自55个个体的ipsc衍生的运动神经元，我们研究了CAV1/2表达和增强子变异在ALS表型中的作用。结果：我们报告了ALS患者和对照组在不同死后脑组织和三个独立数据集中CAV1和CAV2基因的差异表达分析。与对照组相比，ALS患者中CAV1和CAV2的表达始终较高，在初级运动皮层、外侧运动皮层和小脑中均有显著结果。我们还发现，与MinE项目中的非携带者相比，CAV1/2增强子突变携带者的生存率增加，并且ALSFRS测量的进展速度较慢。携带者的平均生存期增加了345天。讨论：这些结果增加了CAV1和CAV2基因与ALS联系的证据。我们提出，CAV1/2增强子突变的携带者可以被定义为一种ALS亚型，其ALS表型较轻，生存时间较长，进展较慢。在ALS病例中，CAV1/2基因的上调可能提示了一种因果途径或代偿机制。鉴于先前的研究支持CAV1/2表达在ALS患者中的有益作用，我们考虑一种代偿机制来更好地适应现有的证据，尽管需要进一步研究与CAV1/2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.
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影响因子：
4.8
作者：
Egawa, Junji;Schilling, Jan M.;Head, Brian P.
通讯作者：
Head, Brian P.
影响因子：
10.6
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Mandyam CD;Schilling JM;Cui W;Egawa J;Niesman IR;Kellerhals SE;Staples MC;Busija AR;Risbrough VB;Posadas E;Grogman GC;Chang JW;Roth DM;Patel PM;Patel HH;Head BP
通讯作者：
Head BP
影响因子：
4.8
作者：
Sawada, Atsushi;Wang, Shanshan;Head, Brian P.
通讯作者：
Head, Brian P.
影响因子：
4.8
作者：
Iacoangeli A;Fogh I;Selvackadunco S;Topp SD;Shatunov A;van Rheenen W;Al-Khleifat A;Opie-Martin S;Ratti A;Calvo A;UK Brain Expression Consortium;Van Damme P;Robberecht W;Chio A;Dobson RJ;Hardiman O;Shaw CE;van den Berg LH;Andersen PM;Smith BN;Silani V;Veldink JH;Breen G;Troakes C;Al-Chalabi A;Jones AR
通讯作者：
Jones AR
影响因子：
7.7
作者：
Conlon EG;Fagegaltier D;Agius P;Davis-Porada J;Gregory J;Hubbard I;Kang K;Kim D;New York Genome Center ALS Consortium;Phatnani H;Shneider NA;Manley JL
通讯作者：
Manley JL