Ethnic Variation and Structure‐Function Analysis of Tauopathy‐Associated PERK Alleles

IF 2.3 4区 化学 Q3 CHEMISTRY, MULTIDISCIPLINARY
Goonho Park, Angela Galdamez, Keon‐Hyoung Song, Masako Le, Kyle Kim, Jonathan H. Lin
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引用次数: 0

Abstract

EIF2AK3, also known as PERK, plays a pivotal role in cellular proteostasis, orchestrating the Unfolded Protein Response (UPR) and Integrated Stress Response (ISR) pathways. In addition to its central position in intracellular stress regulation, human GWAS identify EIF2AK3 as a risk factor in tauopathies, neurodegenerative diseases caused by aberrant tau protein accumulation. Guided by these genomic indicators, our investigation systematically analyzed human PERK variants, focusing on those with potential tauopathy linkages. We assembled a comprehensive data set of human PERK variants associated with Wolcott Rallison Syndrome (WRS), tauopathies, and bioinformatically predicted loss‐of‐function, referencing the gnomAD, Ensembl, and NCBI databases. We found extensive racial/ethnic variation in the prevalence of common PERK polymorphisms linked to tauopathies. Using SWISS‐MODEL, we identified structural perturbations in the ER stress‐sensing luminal domain dimers/oligomers of tauopathy‐associated PERK variants, Haplotypes A and B, in combination with another tauopathy‐linked R240H mutation. Recombinant expression of disease‐associated variants in vitro revealed altered PERK signal transduction kinetics in response to ER stress compared to the predominant non‐disease variant. In summary, our data further substantiates that human PERK variants identified in tauopathy genetic studies negatively impact PERK structure, function, and downstream signaling with significant variations in prevalence among different racial and ethnic groups.
与 Tauopathy 相关的 PERK 等位基因的种族差异和结构功能分析
EIF2AK3 又称 PERK,在细胞蛋白稳态中发挥着关键作用,协调着折叠蛋白反应(UPR)和综合应激反应(ISR)途径。除了在细胞内应力调控中的核心地位外,人类 GWAS 还发现 EIF2AK3 是 tau 病(由 tau 蛋白异常积累引起的神经退行性疾病)的风险因素。在这些基因组指标的指导下,我们的研究对人类 PERK 变异进行了系统分析,重点关注那些与牛头蛋白病有潜在联系的变异。我们参考 gnomAD、Ensembl 和 NCBI 数据库,收集了与 Wolcott Rallison 综合征(WRS)、tauopathies 和生物信息学预测的功能缺失相关的人类 PERK 变异的综合数据集。我们发现,与陶陶病相关的常见 PERK 多态性的发生率存在广泛的种族/民族差异。利用 SWISS-MODEL,我们确定了与牛磺酸脑病相关的 PERK 变体 Haplotypes A 和 B 与另一种与牛磺酸脑病相关的 R240H 突变相结合的 ER 应激传感腔域二聚体/高聚体的结构扰动。在体外重组表达疾病相关变体时发现,与占主导地位的非疾病变体相比,PERK 信号转导动力学对 ER 压力的响应发生了改变。总之,我们的数据进一步证实,在牛磺酸脑病基因研究中发现的人类 PERK 变异对 PERK 的结构、功能和下游信号转导产生了负面影响,而且在不同种族和民族群体中的发生率存在显著差异。
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来源期刊
Israel Journal of Chemistry
Israel Journal of Chemistry 化学-化学综合
CiteScore
6.20
自引率
0.00%
发文量
62
审稿时长
6-12 weeks
期刊介绍: The fledgling State of Israel began to publish its scientific activity in 1951 under the general heading of Bulletin of the Research Council of Israel, which quickly split into sections to accommodate various fields in the growing academic community. In 1963, the Bulletin ceased publication and independent journals were born, with Section A becoming the new Israel Journal of Chemistry. The Israel Journal of Chemistry is the official journal of the Israel Chemical Society. Effective from Volume 50 (2010) it is published by Wiley-VCH. The Israel Journal of Chemistry is an international and peer-reviewed publication forum for Special Issues on timely research topics in all fields of chemistry: from biochemistry through organic and inorganic chemistry to polymer, physical and theoretical chemistry, including all interdisciplinary topics. Each topical issue is edited by one or several Guest Editors and primarily contains invited Review articles. Communications and Full Papers may be published occasionally, if they fit with the quality standards of the journal. The publication language is English and the journal is published twelve times a year.
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