Cellular mechanisms of neuronal dysfunction in addiction and neurodegeneration

National Institute On Drug Abuse

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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 are studying exodosis in relation to the KDEL receptor proteins and how they impact protein secretion under cellular stress. We published a study describing the exodosis phenomenon occurs during glutamate excitotoxicity. This appears to be the first study to show that glutamate can alter secretion of ER resident proteins. We have a manuscript in preparation describing the impact of elevating KDELR expression in specific neurons in the rat brain and their impact on neuronal function. We have an additional manuscript in preparation describing KDELR isoform differences in human neuronal cells. In collaboration with NCATS, we have developed a novel way of analyzing hits from a phenotype-based high throughput drug screen to identify the putative protein targets. We identified the histamine receptor as a target for modulating exodosis. This paper has been deposited on biorxiv and is under revision. In collaboration with Dr. Nigel Greig at NIA IRP, the LINGO1 gene was identified as a candidate drug target for Alzheimer's Disease. This work has now been published. In collaboration with Dr. Merja Voutilainen at U Helsinki, we show that AAV-mediated gene transfer of CDNF protects dopamine neurons and regulates ER stress and inflammation in an acute MPTP mouse model of Parkinson's disease. This work has been published.