IgGs from patients with amyotrophic lateral sclerosis and diabetes target Ca-v alpha(2)delta 1 subunits impairing islet cell function and survivalopen access
- Authors
- Shi, Yue; Park, Kyoung Sun; Kim, Seung Hyun; Yu, Jia; Zhao, Kaixuan; Yu, Lina; Oh, Ki Wook; Lee, Kayoung; Kim, Jaeyoon; Chaggar, Kanchan; Li, Yuxin; Dolphin, Annette C.; Catterall, William A.; Ryu, Sung Ho; Yang, Shao-Nian; Berggren, Per-Olof
- Issue Date
- Dec-2019
- Publisher
- NATL ACAD SCIENCES
- Keywords
- amyotrophic lateral sclerosis; calcium channel; cytosolic free Ca2+ concentration; diabetes; immunoglobulin
- Citation
- PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, v.116, no.52, pp.26816 - 26822
- Indexed
- SCIE
SCOPUS
- Journal Title
- PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
- Volume
- 116
- Number
- 52
- Start Page
- 26816
- End Page
- 26822
- URI
- https://scholarworks.bwise.kr/hanyang/handle/2021.sw.hanyang/146711
- DOI
- 10.1073/pnas.1911956116
- ISSN
- 0027-8424
- Abstract
- 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+],) 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-v alpha(2)delta 1 in the plasma membrane enhancing Ca(v)1 channel-mediated Ca2+ influx and [Ca2+](i), resulting in impaired mitochondria! 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-v alpha(2)delta 1 subunits. Our findings may lay the foundation for a pharmacological treatment strategy for patients suffering from a combination of these diseases.
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