Research ReportDopaminergic neurotoxicity of HIV-1 gp120: Reactive oxygen species as signaling intermediates
Introduction
Parkinson's disease (PD) is characterized by motor, cognitive, and psychiatric disturbances. These include apathy, slow movement and thought, impaired gait, rigidity and others, and largely reflect the consequences of loss of dopaminergic neurons (DNs) from the substantia nigra (SN). The causes of most cases of PD are unknown, but progressive loss of DNs often involves continuing oxidant damage to DN proteins, accumulation of these abnormally modified proteins and consequent disruption of neuronal function (Bernheimer et al., 1973, Hornykiewicz, 2001, Zhang and Kaufman, 2006, Gorman, 2008, Levy et al., 2009).
Ongoing oxidative neuronal injury is also characteristic of symptomatic HIV-1 infection in the CNS, i.e., neuroAIDS (Steiner et al., 2006). HIV-1 enters the CNS shortly after entering the body and replicates in macrophages and microglia there (Gartner, 2000, Rausch et al., 1999). Although highly active antiretroviral therapy (HAART) generally does not penetrate the CNS well and may not greatly impair replication of HIV-1 within the CNS (McArthur et al., 1999), HAART exposure may decrease CNS virus load (Sinclair et al., 2008). The consequences of CNS HIV-1 infection reflect in a major way the neurotoxicity of two HIV-1 protein products, envelope gp120 (Env) and Tat (Kruman et al., 1998, Shi et al., 1998, Corasaniti et al., 1998a, Rappaport et al., 1999, Nath et al., 2000a, Corasantini et al., 2001). Although frank HIV-1-associated dementia is now rare in the US, minor cognitive and motor dysfunction (MCMD) is common. As life expectancies improve for HIV-1-positive patients whose peripheral HIV-1 loads are controlled with HAART, prevalence of MCMD is rising (Sacktor et al., 2002, McArthur et al., 2005).
The pathogenesis of neuronal injury leading to symptomatic neuroAIDS is complex and involves neuronal loss (Navia and Rostasy, 2005, Everall et al., 2005, Langford et al., 2003, Gonzalez-Scarano and Martin-Garcia, 2005, Kaul et al., 2005, Rumbaugh and Nath, 2006, Lawrence and Major, 2002) and dysfunction due to excitotoxic activation of synaptic glutamate receptors, proinflammatory cytokines, proapoptotic signaling elicited by gp120 and Tat in neurons and other factors (Kruman et al., 1998, Shi et al., 1998, Corasaniti et al., 1998b, Rappaport et al., 1999, Nath et al., 2000a, Corasantini et al., 2001, Watanabe et al., 2003, Betz et al., 1998). Several of these mechanisms involve generation of reactive oxygen (ROS) and nitrogen (RNS), causing oxidative damage to many cellular macromolecules, especially lipids and proteins (Turchan et al., 2003, Bandaru et al., 2007, Mattson et al., 2005, Steiner et al., 2006). Gene delivery of Cu/Zn superoxide dismutase (SOD1) and/or glutathione peroxidase (GPx1) to neurons using recombinant SV40-derived vectors (rSV40s) can protect neurons from the toxicity of gp120 and Tat in vitro and in vivo (Agrawal et al., 2006, Agrawal et al., 2007, Louboutin et al., 2007a, Louboutin et al., 2007b).
Interestingly, the symptomatology and pathology of neuroAIDS both reflect disproportionate damage to the dopaminergic system of the SN. Thus, the bradykinesia, bradyphrenia, abnormalities of gait, rigidity, and other characteristics of Parkinson's disease also characterize neuroAIDS (Nath et al., 2000b, Berger and Arendt, 2000, Koutsilieri et al., 2002a, Koutsilieri et al., 2002b, Chang et al., 2008, Khanlou et al., 2009). Disproportionate DN loss is common in neuroAIDS, as are decreased dopamine (DA) and DA metabolites (Reyes et al., 1991, Silvers et al., 2006). Tyrosine hydroxylase (TH), which is critical for DA synthesis, and DA transporter (DAT), which is important for DA reuptake into DN, are often decreased also (Itoh et al., 2000, Wang et al., 2004, Silvers et al., 2007).
Compared to non-dopaminergic neurons (RNs), DNs are reported to be nonspecifically more sensitive to oxidative damage (Fahn and Cohen, 1992, Jenner, 2003), particularly via damage to their mitochondria (Ben-Shachar et al., 1995, Gluck and Zeevalk, 2004). However, the basis for the predilection for DN injury and loss in neuroAIDS has been unclear. We report here that DNs are nonspecifically more susceptible than non-dopaminergic neurons to ROS-induced apoptosis but that, as well, gp120 toxicity for DN is largely specific for gp120, reflects gp120-initiated proapoptotic signaling, localizes mainly to the cytosol, and occurs in DN far more readily than in other neuron types.
ROS are involved in HIV-1 gp120-induced neurotoxicity as signaling intermediates activated by gp120–DN interaction. They may also be direct effectors of oxidant damage. Gp120 is toxic to DN at levels that are innocuous to RN. In addition, it is specifically transported from other areas of the brain to the SN, where it causes selective loss of DN. Antioxidant gene delivery blocks gp120-induced proapoptotic signaling in vitro and protects DN viability in vitro and in vivo.
Section snippets
Cell lines and chemicals
COS-7 cell line was obtained from American Type Culture Collection (ATCC) and maintained in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% calf serum (Hyclone, Logan, UT, USA), 2 mm l-glutamine and containing 1.5 g/l sodium bicarbonate, 4.5 g/l glucose, 1.0 mm sodium pyruvate, penicillin (200 U/ml), and streptomycin (100 g/ml). H2O2 was purchased from Sigma Chemical Co. (St. Louis, MO). Growth factors used as media supplements, epidermal growth factor (EGF), fibroblast growth
Cultured DNs express tyrosine hydroxylase as a marker for DNs and are more sensitive than RNs to oxidative stress
Fully differentiated, DNs were prepared as described in Methods, from 12 to 16-week-old fetal brain, then compared to RNs for expression of the DN marker tyrosine hydroxylase (TH) by immunohistology (Fig. 1a) and Western blotting (Fig. 1b). DNs were positive for TH by both assays, compared to control cultures. On Western analysis, TH was visualized as a prominent band around 65 kDa. These cells were also positive for protein markers such as nestin, NCAM (neuronal cell adhesion molecule), and
Discussion
Gp120 binds neuron cell membrane coreceptors (CCR3, CCR5, CXCR4) and elicits apoptosis (Garden et al., 2004) via G protein-coupled pathways (Kruman, 1998; Kaul and Lipton, 1999). Soluble gp120 also increases glial cell release of arachidonate, which impairs astrocyte and neuron reuptake of glutamate (Lipton et al., 1993) leading to prolonged activation of N-methyl-d-aspartate (NMDA) receptor with consequent disruption of cellular Ca2+ homeostasis (Kaul and Lipton, 2006). A second kind of
Acknowledgments
This work was supported by NIH grant MH70287. We are indebted to the Human Fetal Tissue Bank at Albert Einstein College of Medicine for the primary tissue from which neuron cultures were prepared.
References (76)
- et al.
Preventing HIV-1 Tat-induced apoptosis using antioxidant enzymes: mechanistic and therapeutic implications
Virology
(2007) - et al.
Brain dopamine and the syndromes of Parkinson and Huntington. Clinical, morphological and neurochemical correlations
J. Neurol. Sci.
(1973) - et al.
Gene transfer to rodent brain with recombinant adenoviral vectors: effects of infusion parameters, infectious titer, and virus concentration on transduction volume
Exp. Neurol.
(1998) - et al.
Prostaglandin receptor EP2 protects dopaminergic neurons against 6-OHDA-mediated low oxidative stress
Neurosci. Lett.
(2008) - et al.
Decreased brain dopamine transporters are related to cognitive deficits in HIV patients with and without cocaine abuse
NeuroImage
(2008) - et al.
The HIV envelope protein gp120 in the nervous system
Biochem. Pharmacol.
(1998) - et al.
The HIV envelope protein gp120 in the nervous system: interactions with nitric oxide, interleukin-1beta and nerve growth factor signaling, with pathological implications in vivo and in vitro
Biochem. Pharmacol.
(1998) Oxidant signals and oxidative stress
Curr. Opin. Cell Biol.
(2003)Chemical neuroanatomy of the basal ganglia—normal and in Parkinson's disease
J. Chem. Neuroanat.
(2001)- et al.
HIV-1 protein Tat induces apoptosis of hippocampal neurons by a mechanism involving caspase activation, calcium overload, and oxidative stress
Exp. Neurol.
(1998)
HIV-1 and the brain: connections between HIV-1-associated dementia, neuropathology, and neuroimmunology
Microbes Infect.
Consequences of impaired purine recycling in dopaminergic neurons
Neuroscience
Neurological complications of HIV infection
Lancet Neurol.
X-linked vacuolated myopathy: TNF-alpha and IFN-gamma expression in muscle fibers with MHC class I on sarcolemma
Am. J. Pathol.
Gene transfer to the liver using a replication-deficient recombinant SV40 vector results in long-term amelioration of jaundice in Gunn rats
Gastroenterol
Neurotoxicity of HIV-1 Tat protein: involvement of D1 dopamine receptor
Neurotoxicology
Antioxidant enzyme gene delivery to protect from HIV-1 gp120-induced neuronal apoptosis
Gene Ther.
Dopamine selectively sensitizes dopaminergic neurons to rotenone-induced apoptosis
Neurochem. Res.
Associative and predictive biomarkers of dementia in HIV-1-infected patients
Neurology
Dopamine neurotoxicity: inhibition of mitochondrial respiration
J. Neurochem.
Enhanced ROS production in oncogenically transformed cells potentiates c-Jun N-terminal kinase and p38 mitogen-activated protein kinase activation and sensitization to genotoxic stress
Mol. Cell. Biol.
Envelope glycoprotein gp120 of human immunodeficiency virus type 1 alters ion transport in astrocytes: implications for AIDS dementia complex
Proc. Natl. Acad. Sci. U. S. A.
HIV dementia: the role of the basal ganglia and dopaminergic systems
J. Psychopharm.
Evidence that the HIV-1 coat protein gp120 causes neuronal apoptosis in the neocortex of rat via a mechanism involving CXCR4 chemokine receptor
Neurosci. Lett.
The shifting patterns of HIV encephalitis neuropathology
Neurotox. Res.
The oxidant stress hypothesis in Parkinson's disease: evidence supporting it
Ann. Neurol.
HIV associated neurodegeneration requires p53 in neurons and microglia
FASEB J.
HIV infection and dementia
Science
Inhibition of brain mitochondrial respiration by dopamine and its metabolites: implications for Parkinson's disease and catecholamine-associated diseases
J. Neurochem.
The neuropathogenesis of AIDS
Nat. Rev. Immunol.
Neuronal cell death in neurodegenerative diseases: recurring themes around protein handling
J. Cell. Mol. Med.
Neuronal damage of the substantia nigra in HIV-1 infected brains
Acta Neuropathol.
Oxidative stress in Parkinson's disease
Ann. Neurol.
Chemokines and activated macrophages in HIV gp120-induced neuronal apoptosis
Proc. Natl. Acad. Sci. U. S. A.
Mechanisms of neuronal injury and death in HIV-1 associated dementia
Curr. HIV Res.
HIV-1 infection and AIDS: consequences for the central nervous system
Cell Death Differ.
Increased frequency of α-synuclein in the substantia nigra in human immunodeficiency virus infection
J. Neurovirol.
Use of SV40 to immunize against hepatitis B surface antigen: implications for the use of SV40 for gene transduction and its use as an immunizing agent
Gene Ther.
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