PT  - JOURNAL ARTICLE
AU  - Veronica Granatiero
AU  - Csaba Konrad
AU  - Kirsten Bredvik
AU  - Giovanni Manfredi
AU  - Hibiki Kawamata
TI  - Nrf2 signaling links ER oxidative protein folding and calcium homeostasis in health and disease
AID  - 10.26508/lsa.201900563
DP  - 2019 Oct 01
TA  - Life Science Alliance
PG  - e201900563
VI  - 2
IP  - 5
4099  - https://www.life-science-alliance.org/content/2/5/e201900563.short
4100  - https://www.life-science-alliance.org/content/2/5/e201900563.full
SO  - Life Sci. Alliance2019 Oct 01; 2
AB  - We report a signaling pathway linking two fundamental functions of the ER, oxidative protein folding, and intracellular calcium regulation. Cells sense ER oxidative protein folding through H2O2, which induces Nrf2 nuclear translocation. Nrf2 regulates the expression of GPx8, an ER glutathione peroxidase that modulates ER calcium levels. Because ER protein folding is dependent on calcium, this pathway functions as rheostat of ER calcium levels. Protein misfolding and calcium dysregulation contribute to the pathophysiology of many diseases, including amyotrophic lateral sclerosis, in which astrocytic calcium dysregulation participates in causing motor neuron death. In human-derived astrocytes harboring mutant SOD1 causative of familial amyotrophic lateral sclerosis, we show that impaired ER redox signaling decreases Nrf2 nuclear translocation, resulting in ER calcium overload and increased calcium-dependent cell secretion, leading to motor neuron death. Nrf2 activation in SOD1 mutant astrocytes with dimethyl fumarate restores calcium homeostasis and ameliorates motor neuron death. These results highlight a regulatory mechanism of intracellular calcium homeostasis by ER redox signaling and suggest that this mechanism could be a therapeutic target in SOD1 mutant astrocytes.