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 two studies completed describing the exodosis phenomenon related to glutamate excitoxicity and hyperthermia. These studies are currently in revision stage. 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 posiphen reduces ER stress associated with stroke. This work was published in iScience. We also published a study with Dr. Wang describing an alpha-synuclein antibody that can improve locomotor deficits in a rat model of synucleinopathy. This work was published in Genes.