Cellular mechanisms of neuronal dysfunction in addiction and neurodegeneration

National Institute On Drug Abuse

Investigators

Linked publications & trials

Abstract

We identified a phenomenon in cell biology by which decreases in endoplasmic reticulum calcium levels leads to the secretion of resident proteins of the ER lumen. We show that the cell upregulates KDEL receptor expression to attenuate the loss of these proteins. We coined the term "Exodosis" to refer to the loss of ER resident proteins in response to ER calcium depletion. We had previously created a bioluminescent report of exodosis and used this reporter to create a transgenic mouse that allows us to study exodosis in different tissue types. We published a paper in Transgenic Research this year describing the creation and characterization of this mouse. We also have a study completed describing the exodosis phenomenon related to glutamate excitotoxicity which is under review. As part of a Bench to Bedside project with NINR, we examined exodosis in human muscle cell and identified putative biomarkers for ER/SR calcium dysfunction in muscle. This work was published in Orphanet J Rare Dis. Our group demonstrates that MDMA and caffeine work synergistically to alter ER stress under hyperthermic conditions. This work provides basis for understanding changes to cells in the brain under conditions where environmental temperature is high and MDMA and caffeine are abused. Our group examined how free fatty acids found in some diets can affect ER stress and ER membrane lipid composition. We show that adaptations to ER stress caused by ER calcium depletion have minimal impact on membrane composition of various subcellular compartments despite a robust ER stress response. In contrast, free fatty acids cause robust changes in lipid composition without significantly activating an ER stress response. Our studies were carried out in a human neuronal cell line. The work was published in Biochim Biophys Acta Mol Cell Biol Lipids. We developed a high throughput screen for drugs that can prevent exodosis. We identified both novel and FDA-approved drugs that can attenuate exodosis triggered by ER calcium depletion. One of the FDA-approved drugs we identified is bromocriptine and we showed that the anti-exodosis property is not related to its known action on the dopamine D2 receptor. We also showed that bromocriptine and analogs of bromocriptine can improve outcomes in models of stroke and diabetes. This work was published in Cell Reports and additional compounds are being actively studied. In collaboration with Dr. Yavin Shahams group at NIDA IRP, we helped develop a transgenic rat for expressing Cre recombinase in mu opioid receptor (MOR) expressing cells. This rat is being used by multiple laboratories to study the role of MOR expressing cells in substance use disorder. The paper describing the production and characterization of the rat has been published in the Journal of Neuroscience.