Dopaminergic neurotoxicity of HIV-1 gp120: reactive oxygen species as signaling intermediates.
We examined the role of reactive oxygen species (ROS) in loss of dopaminergic neurons (DNs) from the substantia nigra (SN) in neuroAIDS. The frequency of Parkinson-like symptomatology, and DN loss, in neuroAIDS is often attributed to nonspecific DN fragility to oxidative stress. Cultured DN are more sensitive to ROS than non-dopaminergic neurons (RN): DN underwent apoptosis at far lower H(2)O(2) concentrations than RN. Gene delivery of glutathione peroxidase (GPx1), which detoxifies H(2)O(2), largely protected both neuron types. HIV-1 envelope, gp120, which elicits oxidative stress in neurons, caused apoptosis more readily in DN than in RN. However, unlike apoptosis caused by H(2)O(2), gp120-induced DN apoptosis was specific: DNs were specifically more sensitive than RN to receptor-mediated [Ca(2+)](i) fluxes triggered by gp120. Gp120-induced Ca(2+) signaling in both neuron types was inhibited by GPx1 or Cu/Zn superoxide dismutase (SOD1), implicating superoxide and peroxide in ligand (gp120)-induced signaling upstream of Ca(2+) release from intracellular stores. In vivo, rats given 10 ng of gp120 stereotaxically showed rapid DN loss within the SN, while loss of RN in the SN and caudate-putamen (CP) was slower and required > or =100 ng of gp120. Furthermore, gp120 injected into the CP was transported axonally retrograde to the SN, causing delayed DN loss there. This, too, was prevented by SOD1 or GPx1. DNs are therefore specifically hypersensitive to gp120-induced apoptosis, signaling for which involves ROS intermediates. These findings may help explain why DN loss and Parkinson's-like dysfunction predominate in neuroAIDS and may apply to other neurodegenerative diseases involving the SN.
Agrawal
Lokesh
L
Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA.
Louboutin
Jean-Pierre
JP
Marusich
Elena
E
Reyes
Beverley A S
BA
Van Bockstaele
Elisabeth J
EJ
Strayer
David S
DS
D015526:AIDS Dementia Complex / Q000503:physiopathology / Q000628:therapy; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D019556:COS Cells; D002118:Calcium / Q000378:metabolism; D002421:Caudate Nucleus / Q000503:physiopathology; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D004298:Dopamine / Q000378:metabolism*; D005260:Female; D015316:Genetic Therapy; D005979:Glutathione Peroxidase / Q000235:genetics / Q000627:therapeutic use; D015699:HIV Envelope Protein gp120 / Q000378:metabolism*; D015497:HIV-1; D006861:Hydrogen Peroxide / Q000378:metabolism; D009474:Neurons / Q000502:physiology*; D011699:Putamen / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction; D013378:Substantia Nigra / Q000503:physiopathology*; D013482:Superoxide Dismutase / Q000378:metabolism; D000072105:Superoxide Dismutase-1
D015699:HIV Envelope Protein gp120; D017382:Reactive Oxygen Species; C000606290:SOD1 protein, human; C514793:gp120 protein, Human immunodeficiency virus 1; D006861:Hydrogen Peroxide; D005979:Glutathione Peroxidase; C000606292:Sod1 protein, rat; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D002118:Calcium; D004298:Dopamine