Show simple item record

To Fold or Not to Fold: The Role of Protein Triage in Dictating Neural Cell Fate Following Acute Injury

dc.creatorPalubinsky, Amy Marie
dc.description.abstractNeuronal protein refolding and degradation in response to stress is largely mediated by the HSP70 chaperone complex and is critical for maintaining cell function and survival. While some components of the triage machinery have been identified, we lack both a fundamental understanding of the triage responses that neurons evoke in response to an acute, ischemic stress and an ability to leverage this response to improve protein triage. In this work we have identified changes in known and novel molecules that are part of the chaperone machinery in response to oxygen and glucose deprivation (OGD) that may represent new targets for therapeutic intervention. We find that immediately following a short period of OGD, neurons endogenously attempt to refold damaged proteins but are unable to maintain these increased folding rates. Using an allosteric modulator of the HSP70 complex, 115-7c, which promotes protein refolding, we were able to improve both neuronal protein and lipid integrity. Additionally, cholesterol biosynthesis, bioenergetic status and membrane architecture were all improved by 115-7c while levels of oxidized and ubiquitinated proteins were decreased. Priming naive neurons with 115-7c mimics the endogenous response to low level stress and neuroprotective effects of ischemic preconditioning (PC) in the absence of new protein synthesis. Taken together with our proteomic and metabolic data, we hypothesize that the endogenous response to acute injury is to promote protein refolding and that pharmacological augmentation of this response will allow neurons to better maintain proteostasis, decrease cell injury and maximize energetic capacity in order to survive ischemic stress. Given that stroke is a leading cause of death worldwide, and that there is currently only one FDA-approved treatment for the ischemic stroke, these data are particularly compelling and warrant continued exploration.
dc.subjectProtein Triage
dc.subjectProtein Folding
dc.subjectNeuronal Metabolism
dc.subjectPrimary Neurons
dc.subjectOxygen and Glucose Deprivation
dc.titleTo Fold or Not to Fold: The Role of Protein Triage in Dictating Neural Cell Fate Following Acute Injury
dc.contributor.committeeMemberTyler W Abel
dc.contributor.committeeMemberRebecca M Sappington
dc.contributor.committeeMemberBethAnn McLaughlin
dc.type.materialtext University
dc.contributor.committeeChairEugenia V Gurevich

Files in this item


This item appears in the following Collection(s)

Show simple item record