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Title: HIV-1 Tat activates neuronal ryanodine receptors with rapid induction of the unfolded protein response and mitochondrial hyperpolarization.

Authors: Norman, John P; Perry, Seth W; Reynolds, Holly M; Kiebala, Michelle; De Mesy Bentley, Karen L; Trejo, Margarita; Volsky, David J; Maggirwar, Sanjay B; Dewhurst, Stephen; Masliah, Eliezer; Gelbard, Harris A

Published In PLoS One, (2008)

Abstract: Neurologic disease caused by human immunodeficiency virus type 1 (HIV-1) is ultimately refractory to highly active antiretroviral therapy (HAART) because of failure of complete virus eradication in the central nervous system (CNS), and disruption of normal neural signaling events by virally induced chronic neuroinflammation. We have previously reported that HIV-1 Tat can induce mitochondrial hyperpolarization in cortical neurons, thus compromising the ability of the neuron to buffer calcium and sustain energy production for normal synaptic communication. In this report, we demonstrate that Tat induces rapid loss of ER calcium mediated by the ryanodine receptor (RyR), followed by the unfolded protein response (UPR) and pathologic dilatation of the ER in cortical neurons in vitro. RyR antagonism attenuated both Tat-mediated mitochondrial hyperpolarization and UPR induction. Delivery of Tat to murine CNS in vivo also leads to long-lasting pathologic ER dilatation and mitochondrial morphologic abnormalities. Finally, we performed ultrastructural studies that demonstrated mitochondria with abnormal morphology and dilated endoplasmic reticulum (ER) in brain tissue of patients with HIV-1 inflammation and neurodegeneration. Collectively, these data suggest that abnormal RyR signaling mediates the neuronal UPR with failure of mitochondrial energy metabolism, and is a critical locus for the neuropathogenesis of HIV-1 in the CNS.

PubMed ID: 19009018 Exiting the NIEHS site

MeSH Terms: AIDS Dementia Complex/pathology; Animals; Calcium/metabolism; Cerebral Cortex/cytology; Cerebral Cortex/ultrastructure; Endoplasmic Reticulum/drug effects; Endoplasmic Reticulum/pathology; Endoplasmic Reticulum/ultrastructure; Humans; Ion Channel Gating/drug effects*; Male; Membrane Potential, Mitochondrial/drug effects*; Mice; Mice, Inbred C57BL; Mitochondria/drug effects; Mitochondria/metabolism*; Mitochondrial Membranes/drug effects; Mitochondrial Membranes/metabolism; Mitochondrial Membranes/ultrastructure; Neurons/drug effects; Neurons/metabolism*; Neurons/pathology; Neurons/ultrastructure; Protein Folding/drug effects*; Protein Transport/drug effects; Rats; Rats, Sprague-Dawley; Ryanodine Receptor Calcium Release Channel/metabolism*; Up-Regulation/drug effects; tat Gene Products, Human Immunodeficiency Virus/pharmacology*

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