Cellular mechanisms of neuronal dysfunction in addiction and neurodegeneration

National Institute On Drug Abuse

Investigators

Linked publications & trials

Abstract

We identified a novel 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 have a study completed describing the exodosis phenomenon related to glutamate excitoxicity which is under review. We also published an invited review on KDEL receptors and their role in the unfolded protein response in J Intl Mol Sci. 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 effect 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. In collaboration with Lei Shi (NIDA), we used machine-based learning to predict carboxy-terminal peptide sequences for proteins that reside in the endoplasmic reticulum and undergo exodosis in response to ER calcium depletion. This work is published in Frontiers in Chemistry. In collaboration with Dr. Mikko Airavaara (U Helsinki), we examined the effects of the neurotrophic protein MANF on the transcriptional profile of rat brain tissue following an ischemic event. We gained new insight into how MANF can promote neuroprotection and neuroregeneration. This work was published in Experimental Neurology. In collaboration with Dr. Yun Wang (NHRI), we published a study showing that an AAV vector expressing an antibody to alpha-synculein could reduce the pathogenic effects of alpha synuclein expression in the rat brain. This paper was published in Genes.