Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 116, Issue 52, Pages 26816-26822Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1911956116
Keywords
amyotrophic lateral sclerosis; calcium channel; cytosolic free Ca2+ concentration; diabetes; immunoglobulin
Categories
Funding
- Basic Science Research Program of the National Research Foundation of Korea (NRF) - Ministry of Science and Information and Communications Technology [NRF-2016K1A1A2912722]
- Brain Research Program of the National Research Foundation of Korea (NRF) - Ministry of Science and Information and Communications Technology [NRF-2018M3C7A1056512]
- Swedish Diabetes Association
- Funds of Karolinska Institutet
- Swedish Research Council
- Novo Nordisk Foundation
- Erling-Persson Family Foundation
- Strategic Research Program in Diabetes at Karolinska Institutet
- European Research Council [ERC-2013-AdG 338936-BetaImage]
- Knut and Alice Wallenberg Foundation
- Skandia Insurance Company, Ltd.
- Diabetes and Wellness Foundation
- Bert von Kantzow Foundation
- Lee Kong Chian School of Medicine
- Nanyang Technological University (Start-Up Grant)
- Stichting af Jochnick Foundation
- Wellcome Trust Investigator Award [098360/Z/12/Z]
- Wellcome Trust [098360/Z/12/Z] Funding Source: Wellcome Trust
Ask authors/readers for more resources
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available