Journal article
Neuronal ferritin heavy chain and drug abuse affect HIV-associated cognitive dysfunction
The Journal of clinical investigation, v 124(2), pp 656-669
03 Feb 2014
PMID: 24401274
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Interaction of the chemokine CXCL12 with its receptor CXCR4 promotes neuronal function and survival during embryonic development and throughout adulthood. Previous studies indicated that μ-opioid agonists specifically elevate neuronal levels of the protein ferritin heavy chain (FHC), which negatively regulates CXCR4 signaling and affects the neuroprotective function of the CXCL12/CXCR4 axis. Here, we determined that CXCL12/CXCR4 activity increased dendritic spine density, and also examined FHC expression and CXCR4 status in opiate abusers and patients with HIV-associated neurocognitive disorders (HAND), which is typically exacerbated by illicit drug use. Drug abusers and HIV patients with HAND had increased levels of FHC, which correlated with reduced CXCR4 activation, within cortical neurons. We confirmed these findings in a nonhuman primate model of SIV infection with morphine administration. Transfection of a CXCR4-expressing human cell line with an iron-deficient FHC mutant confirmed that increased FHC expression deregulated CXCR4 signaling and that this function of FHC was independent of iron binding. Furthermore, examination of morphine-treated rodents and isolated neurons expressing FHC shRNA revealed that FHC contributed to morphine-induced dendritic spine loss. Together, these data implicate FHC-dependent deregulation of CXCL12/CXCR4 as a contributing factor to cognitive dysfunction in neuroAIDS.
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Details
- Title
- Neuronal ferritin heavy chain and drug abuse affect HIV-associated cognitive dysfunction
- Creators
- Jonathan Pitcher - Department of Pharmacology and PhysiologyAnna Abt - Department of Pharmacology and PhysiologyJaclyn Myers - Department of Pharmacology and PhysiologyRachel Han - Department of Pharmacology and PhysiologyMelissa Snyder - Department of Pharmacology and PhysiologyAlessandro Graziano - Department of Pharmacology and PhysiologyLindsay Festa - Department of Pharmacology and PhysiologyMichele Kutzler - Department of Pharmacology and PhysiologyFernando Garcia - Department of Pharmacology and PhysiologyWen-Jun Gao - Department of Pharmacology and PhysiologyTracy Fischer-Smith - Department of Pharmacology and PhysiologyJay Rappaport - Department of Pharmacology and PhysiologyOlimpia Meucci - Department of Pharmacology and Physiology
- Publication Details
- The Journal of clinical investigation, v 124(2), pp 656-669
- Publisher
- American Society for Clinical Investigation
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Neurobiology and Anatomy; Pharmacology and Physiology; Infectious Diseases (and HIV Medicine)
- Web of Science ID
- WOS:000331413300025
- Scopus ID
- 2-s2.0-84893854318
- Other Identifier
- 991014877954204721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Medicine, Research & Experimental