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

Mishra, Mamata; Vetrivel, S.; Siddappa, Nagadenahalli B.; Ranga, Udaykumar; Seth, Pankaj

doi:10.1002/ana.21292

Cited by 116 publications

(143 citation statements)

References 46 publications

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“…This was further confirmed by site specific mutagenesis in which we mutated the Cys31 in clade B Tat to a Ser and mutated Ser31 to Cys in clade C Tat and then compared their neurotoxic potential. This is consistent with a recent study that implicated the role of Cys31 in Tat-mediated neurotoxicity in primary neurons (Mishra et al, 2008). Interestingly, however, both clade B and C Tat could similarly immunoprecipitate the NMDA receptor.…”

Section: Discussionsupporting

confidence: 92%

NMDA Receptor Activation by HIV-Tat Protein Is Clade Dependent

Li¹,

et al. 2008

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Section: Discussionsupporting

confidence: 92%

NMDA Receptor Activation by HIV-Tat Protein Is Clade Dependent

Li¹,

et al. 2008

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“…These primary neurons express tyrosine hydroxylase and most of the Tuj1 positive neurons also express tyrosine hydroxylase (supplemental Fig. 1 A, available at www.jneurosci.org as supplemental material) indicating the predominant dopaminergic phenotype of these cells (Mishra et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

“…Human CNS progenitor cell cultures were prepared from 8-to 12-week-old embryos obtained from elective medical termination of first trimester pregnancies performed at the local hospital after informed consent as per the approved protocol of the institutional human ethics committee in compliance with the recommendations of the Indian Council of Medical Research, Government of India. Primary cultures of human CNS progenitor cells were prepared and cultured as monolayers on poly-Dlysine coated chamber slides in serum-free neurobasal medium and neurons were derived from them as described previously (Mishra et al, 2008). Neuronal differentiation involved changing the growth factors in the progenitor media to brain-derived neurotrophic factor (BDNF, 10 ng/ml) and platelet-derived growth factor (PDGF)-A/B (10 ng/ml) for 3 weeks.…”

Section: Methodsmentioning

confidence: 99%

Selective Activation of p38 Mitogen-Activated Protein Kinase in Dopaminergic Neurons of Substantia Nigra Leads to Nuclear Translocation of p53 in 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine-Treated Mice

Karunakaran¹,

Saeed²,

Mishra³

et al. 2008

J. Neurosci.

123

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Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by the degeneration of the dopaminergic neurons in the substantia nigra pars compacta (SNpc). Activation of the mixed lineage kinase and c-Jun N-terminal kinase (JNK) has been reported in models of PD. Our focus was to discern whether distinct pathways were activated in cell-specific manner within the SNpc. We now demonstrate the selective phosphorylation of p38 MAP kinase within the dopaminergic neurons, whereas JNK activation occurs predominantly in the microglia. p38 activation results in downstream phosphorylation of p53 and increased p53 mediated transcription of Bax and Puma in the ventral midbrain. Treatment with p38 inhibitor, SB239063 protected primary dopaminergic neurons derived from human progenitor cells from MPP ϩ mediated cell death and prevented the downstream phosphorylation of p53 and its translocation to the nucleus in vivo, in the ventral midbrain. The increased staining of phosphorylated p38 in the surviving neurons of SNpc in human brain sections from patients with PD and in MPTP treated mice but not in the ventral tegmental area provides further evidence suggesting a role for p38 in the degeneration of dopaminergic neurons of SNpc. We thus demonstrate the cell specific activation of MAP kinase pathways within the SNpc after MPTP treatment emphasizing the role of multiple signaling cascades in the pathogenesis and progression of the disease. Selective inhibitors of p38 may therefore, help preserve the surviving neurons in PD and slow down the disease progression.

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“…41 It has been found that tat expression differs between HIV clades, and further proposed that a defect in the dicysteine motif in tat in clade C leads to lower levels of neurotoxicity. 42 The implications are that in regions where clade C is predominant, such as South Africa, lower rates of HAND might be expected. Recent work in India, where clade C is also predominant has not supported this idea.…”

Section: Mechanisms Of Neuro-degenerationmentioning

confidence: 99%

“…[23][24][25] Variability has been attributed to differences in the dicysteine motif within the neurotoxic region of B-Tat, producing a greater degree of Tat-induced apoptosis. 26,27 However, other viral proteins, such as gp120, may be as neurotoxic. The clade sequence, levels of proviral DNA and tat protein, together with their impact on neuropsychological functions and neuro-imaging findings, is the subject of a study currently being conducted by our group.…”

Section: Introductionmentioning

confidence: 99%

The neurobiology of HIV dementia: implications for practice in South Africa

Joska¹,

Hoare²,

Stein³

et al. 2011

Afr. J. Psych

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In this review, the neuropathogenesis of HIV dementia (HIV-D) is discussed in the context of the local epidemic. HIV-D continues to be prevalent in the era of highly active anti-retroviral therapy. HIV neuro-invasion into the central nervous system may result in the development of separate HIV genotypes in an individual through compartmentalisation. The blood brain barrier continues to limit penetration of anti-retroviral drugs into the cerebrospinal fluid. Individuals with active neuro-inflammation appear to respond well to HAART. In some cases low grade neuro-degeneration persists with consequent clinical deterioration. In South Africa, the emergence of a sub-epidemic of HIV-D is being driven by various factors, including the incomplete coverage of HAART to all who need it, the late stage presentation of people living with HIV/AIDS (PLWHA) and a co-occurring methamphetamine epidemic. Differences in viral subtype do not appear to confer protection against HIV-D. Implications for PLWHA who are at risk for HIV-D in South Africa are explored, with a view to providing suggestions for improving practice and research into this area.

show abstract

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

Cited by 116 publications

References 46 publications

NMDA Receptor Activation by HIV-Tat Protein Is Clade Dependent

NMDA Receptor Activation by HIV-Tat Protein Is Clade Dependent

Selective Activation of p38 Mitogen-Activated Protein Kinase in Dopaminergic Neurons of Substantia Nigra Leads to Nuclear Translocation of p53 in 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine-Treated Mice

The neurobiology of HIV dementia: implications for practice in South Africa

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