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标题：IgGs from patients with amyotrophic lateral sclerosis and diabetes target CaVα2δ1 subunits impairing islet cell function and survival
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作者：Yue Shi ; Kyoung Sun Park ; Seung Hyun Kim 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2019
卷号：116
期号：52
页码：26816-26822
DOI：10.1073/pnas.1911956116
出版社：The National Academy of Sciences of the United States of America
摘要：Patients with amyotrophic lateral sclerosis (ALS) often show hallmarks of type 2 diabetes mellitus (T2DM). However, the causal link between ALS and T2DM has remained a mystery. We now demonstrate that 60% of ALS patients with T2DM (ALS-T2DM) have sera that exaggerated K⁺-induced increases in cytosolic free Ca²⁺ concentration ([Ca²⁺]_i) in mouse islet cells. The effect was attributed to the presence of pathogenic immunoglobulin Gs (IgGs) in ALS-T2DM sera. The pathogenic IgGs immunocaptured the voltage-dependent Ca²⁺ (Ca_V) channel subunit Ca_Vα₂δ1 in the plasma membrane enhancing Ca_V1 channel-mediated Ca²⁺ influx and [Ca²⁺]_i, resulting in impaired mitochondrial function. Consequently, impairments in [Ca²⁺]_i dynamics, insulin secretion, and cell viability occurred. These data reveal that patients with ALS-T2DM carry cytotoxic ALS-T2DM-IgG autoantibodies that serve as a causal link between ALS and T2DM by immunoattacking Ca_Vα₂δ1 subunits. Our findings may lay the foundation for a pharmacological treatment strategy for patients suffering from a combination of these diseases.
关键词：amyotrophic lateral sclerosis ; calcium channel ; cytosolic free Ca²⁺ concentration ; diabetes ; immunoglobulin