Apoptotic death of striatal neurons induced by human immunodeficiency virus-1 Tat and gp120: Differential involvement of caspase-3 and endonuclease G

Singh, Indrapal N.; Goody, Robin J; Dean, Celeste; Ahmad, Nael M; Lutz, Sarah E.; Knapp, Pamela E.; Nath, Avindra; Hauser, Kurt F.

doi:10.1080/13550280490441103

Cited by 109 publications

(121 citation statements)

References 83 publications

(101 reference statements)

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“…After 6-8 days in vitro, neuron-enriched cultures of mouse striata were continuously exposed for 0-72 h with HIV-1 Tat (100 nM) or gp120 (500 pM) applied extracellularly. Striatal cultures consist of ~97% neurons, and most of these are spiny projection neurons (medium spiny neurons) (Gerfen and Wilson, 1996), as determined using previously described morphological and immunocytochemical criteria Singh et al, 2004). To inhibit p38 and JNK1/2 MAPKs, respectively, cells were pretreated for 60 min with SB203580 (10 µM; Tocris Cookson, Inc.; Ellisville, MO) or SP600125 (10 µM; Biosource International, Camarillo, CA).…”

Section: Isolation and Treatment Of Striatal Neuron Culturesmentioning

confidence: 99%

“…Neuron viability was assessed by repeatedly photographing the same neurons at 24 h intervals before/after experimental treatments using an inverted microscope with phase contrast optics and 40× objective as previously described (Singh et al, 2004). Neuron death was defined by rigorous criteria, including dissolution of Nissl substance, cytoplasmic swelling and vacuolization, and eventual fragmentation of the cell body (Singh et al, 2004).…”

Section: Neuron Viabilitymentioning

confidence: 99%

“…Highly-enriched, striatal neuronal cultures from embryonic day 14 (E14) ICR mice were prepared in accordance with NIH Guidelines and following approval by the local IACUC as previously described Singh et al, 2003;Singh et al, 2004), which includes efforts to use the minimum number of mice possible and any potential discomfort. Fetal striata were dissected and striatal cells isolated and grown for 6 to 8 days in vitro (DIV) prior to assay in serum-free DMEM/F-12 medium supplemented with 2% B-27, 1 µg/ml linoleic acid, 25-µg/ml insulin, and 1% antibiotic/antimycotic.…”

Section: Isolation and Treatment Of Striatal Neuron Culturesmentioning

confidence: 99%

“…Neuron death was defined by rigorous criteria, including dissolution of Nissl substance, cytoplasmic swelling and vacuolization, and eventual fragmentation of the cell body (Singh et al, 2004).…”

Section: Neuron Viabilitymentioning

confidence: 99%

“…Inhibition of p38 MAPK reduces gp120 toxicity in human neurons (Hu et al, 2005). Extracellular Tat likely causes death in striatal neurons through multiple apoptotic pathways (Singh et al, 2004), which may differ among different cell and neuronal types.…”

Section: Introductionmentioning

confidence: 99%

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Differential involvement of p38 and JNK MAP kinases in HIV-1 Tat and gp120-induced apoptosis and neurite degeneration in striatal neurons

et al. 2005

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The role of p38 and c-jun-N-terminal kinases 1/2 (JNK), members of the mitogen-activated protein kinase (MAPK) family, in mediating the toxic effects of HIV-1 Tat and gp120 were explored in primary mouse striatal neurons in vitro. Both Tat and gp120 caused significant increases in p38 and JNK MAPK phosphorylation, caspase-3 activity, neurite losses and cell death in striatal neurons. Tat-induced increases in caspase-3 activity were significantly attenuated by an inhibitor of JNK (SP600125), but not by an inhibitor of p38 (SB203580), MAPK. However, despite preventing increases in caspase-3 activity, JNK inhibition failed to avert Tat-induced neuronal losses suggesting that the reductions in caspase-3 activity were insufficient to prevent cell death caused by Tat. Alternatively, gp120-induced increases in caspase-3 activity, neurite losses and neuronal death were prevented by p38, but not JNK, MAPK inhibition. Our findings suggest that gp120 induces neuronal dysfunction and death through actions at p38 MAPK, while Tat kills neurons through actions that are independent of p38 or JNK MAPK, or through the concurrent activation of multiple proapoptotic pathways.

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Section: Isolation and Treatment Of Striatal Neuron Culturesmentioning

confidence: 99%

Section: Neuron Viabilitymentioning

confidence: 99%

Section: Isolation and Treatment Of Striatal Neuron Culturesmentioning

confidence: 99%

Section: Neuron Viabilitymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Differential involvement of p38 and JNK MAP kinases in HIV-1 Tat and gp120-induced apoptosis and neurite degeneration in striatal neurons

et al. 2005

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Clade‐specific differences in neurotoxicity of human immunodeficiency virus‐1 B and C Tat of human neurons: significance of dicysteine C30C31 motif

Mishra

Vetrivel²,

Siddappa

et al. 2008

Annals of Neurology

118

133

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HIV‐1 Tat‐induced bystander apoptosis in Jurkat cells involves unfolded protein responses

Campestrini

Silveira

Pinto

2018

Cell Biochemistry & Function

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The HIV transactivator protein (Tat) is a multifunctional protein that plays a critical role in viral replication and contributes to several pathological symptoms of HIV‐1 infection, which has the loss of CD4+ T lymphocytes as one of its hallmark features. It has been shown that endoplasmic reticulum (ER) stress, including viral infections, is implicated in cellular dysfunction and cell death through activation of the unfolded protein response (UPR). Here, we demonstrate that the bystander stimulus of Tat on Jurkat cells resulted in time‐dependent overexpression of major UPR markers including ER chaperone BiP, ER stress sensors ATF6, PERK, and IRE1, as well as an increase in levels of downstream mediators eIF2α, ATF4, XBP‐1, and proapoptotic factors CHOP, GADD34, and BIM. This upregulation of UPR mediators was accompanied by decreased cell viability and increased apoptosis as evidenced by blue trypan dye exclusion and flow cytometry assays, respectively. Furthermore, we found that the Tat‐associated apoptosis of Jurkat cells led to the loss of mitochondrial membrane potential and caspase‐12 and ‐3 activation. Taken together, these results suggest that the exposure of HIV‐1 Tat leads to ER stress/UPR triggering which in turn contributes to apoptotic death in Jurkat cells. Significance of the study In the present work, we provide a substantial insight into the link between ER impairment and apoptotic death following a bystander HIV Tat stimulus, revealing an underlying ER‐mediated apoptotic mechanism which could explain the continuous depletion of uninfected CD4+ T lymphocytes observed in HIV‐related disease. Our findings reinforce the relevance of ER stress molecular responses in the course of HIV infection and may afford valuable information for the development of new therapeutic strategies to avoid CD4+ T lymphocyte loss and other disorders induced by circulant Tat.

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Apoptotic death of striatal neurons induced by human immunodeficiency virus-1 Tat and gp120: Differential involvement of caspase-3 and endonuclease G

Cited by 109 publications

References 83 publications

Differential involvement of p38 and JNK MAP kinases in HIV-1 Tat and gp120-induced apoptosis and neurite degeneration in striatal neurons

Differential involvement of p38 and JNK MAP kinases in HIV-1 Tat and gp120-induced apoptosis and neurite degeneration in striatal neurons

Clade‐specific differences in neurotoxicity of human immunodeficiency virus‐1 B and C Tat of human neurons: significance of dicysteine C30C31 motif

HIV‐1 Tat‐induced bystander apoptosis in Jurkat cells involves unfolded protein responses

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