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IgGs from patients with amyotrophic lateral sclerosis and diabetes target CaVα2δ1 subunits impairing islet cell function and survival

Shi, Y; Park, KS; Kim, SH; Yu, J; Zhao, K; Yu, L; Oh, KW; ... Berggren, P-O; + view all (2019) IgGs from patients with amyotrophic lateral sclerosis and diabetes target CaVα2δ1 subunits impairing islet cell function and survival. Proceedings of the National Academy of Sciences (PNAS) 10.1073/pnas.1911956116. (In press). Green open access

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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+]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+ (CaV) channel subunit CaVα2δ1 in the plasma membrane enhancing CaV1 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 CaVα2δ1 subunits. Our findings may lay the foundation for a pharmacological treatment strategy for patients suffering from a combination of these diseases.

Type: Article
Title: IgGs from patients with amyotrophic lateral sclerosis and diabetes target CaVα2δ1 subunits impairing islet cell function and survival
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1073/pnas.1911956116
Publisher version: https://doi.org/10.1073/pnas.1911956116
Language: English
Additional information: This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
Keywords: amyotrophic lateral sclerosis, calcium channel, cytosolic free Ca2+ concentration, diabetes, immunoglobulin
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Neuro, Physiology and Pharmacology
URI: https://discovery.ucl.ac.uk/id/eprint/10088146
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