Anumantha G Kanthasamy

Iowa State University, Ames, Iowa, United States

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Publications (142)554.44 Total impact

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    ABSTRACT: Complex biological barriers are major obstacles for preventing and treating disease. Nano-carriers are designed to overcome such obstacles by enhancing drug delivery through physiochemical barriers and improving therapeutic indices. This review critically examines both biological barriers and nano-carrier payloads for a variety of drug delivery applications. A spectrum of nano-carriers is discussed that have been successfully developed for improving tissue penetration for preventing or treating a range of infectious, inflammatory, and degenerative diseases. Copyright © 2015. Published by Elsevier B.V.
    Journal of Controlled Release 08/2015; 219. DOI:10.1016/j.jconrel.2015.08.039 · 7.71 Impact Factor
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    ABSTRACT: We recently identified a compensatory survival role for protein kinase D1 (PKD1) in protecting dopaminergic neurons from oxidative insult. To investigate the molecular mechanism of Prkd1 gene expression, we cloned the 5'-flanking region (1620-bp) of the mouse Prkd1 gene. Deletion analyses revealed that the -250/+113 promoter region contains full promoter activity in MN9D dopaminergic neuronal cells. In silico analysis of the Prkd1 promoter uncovered binding sites for key redox transcription factors including Sp1 and NF-κB. Overexpression of Sp1, Sp3, and NF-κB-p65 proteins stimulated Prkd1 promoter activity. Binding of Sp3 and NF-κB-p65 to the Prkd1 promoter was confirmed using chromatin immunoprecipitation. Treatment with the Sp inhibitor mithramycin-A significantly attenuated Prkd1 promoter activity and PKD1 mRNA and protein expression. Further mechanistic studies revealed that inhibition of histone acetylation and DNA methylation upregulates PKD1 mRNA expression. Importantly, negative modulation of PKD1 signaling by pharmacological inhibition or shRNA knockdown increased dopaminergic neuronal sensitivity to oxidative damage in a human mesencephalic neuronal cell model. Collectively, our findings demonstrate that Sp1, Sp3 and NF-κB-p65 can transactivate the mouse Prkd1 promoter and that epigenetic mechanisms, such as DNA methylation and histone modification, are key regulatory events controlling the expression of pro-survival kinase PKD1 in dopaminergic neuronal cells. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Journal of Neurochemistry 07/2015; 135(2). DOI:10.1111/jnc.13261 · 4.28 Impact Factor
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    ABSTRACT: Unlabelled: Sustained neuroinflammation mediated by resident microglia is recognized as a key pathophysiological contributor to many neurodegenerative diseases, including Parkinson's disease (PD), but the key molecular signaling events regulating persistent microglial activation have yet to be clearly defined. In the present study, we examined the role of Fyn, a non-receptor tyrosine kinase, in microglial activation and neuroinflammatory mechanisms in cell culture and animal models of PD. The well-characterized inflammogens LPS and TNFα rapidly activated Fyn kinase in microglia. Immunocytochemical studies revealed that activated Fyn preferentially localized to the microglial plasma membrane periphery and the nucleus. Furthermore, activated Fyn phosphorylated PKCδ at tyrosine residue 311, contributing to an inflammogen-induced increase in its kinase activity. Notably, the Fyn-PKCδ signaling axis further activated the LPS- and TNFα-induced MAP kinase phosphorylation and activation of the NFκB pathway, implying that Fyn is a major upstream regulator of proinflammatory signaling. Functional studies in microglia isolated from wild-type (Fyn(+/+)) and Fyn knock-out (Fyn(-/-)) mice revealed that Fyn is required for proinflammatory responses, including cytokine release as well as iNOS activation. Interestingly, a prolonged inflammatory insult induced Fyn transcript and protein expression, indicating that Fyn is upregulated during chronic inflammatory conditions. Importantly, in vivo studies using MPTP, LPS, or 6-OHDA models revealed a greater attenuation of neuroinflammatory responses in Fyn(-/-) and PKCδ (-/-) mice compared with wild-type mice. Collectively, our data demonstrate that Fyn is a major upstream signaling mediator of microglial neuroinflammatory processes in PD. Significance statement: Parkinson's disease (PD) is a complex multifactorial disease characterized by the progressive loss of midbrain dopamine neurons. Sustained microglia-mediated neuroinflammation has been recognized as a major pathophysiological contributor to chronic degenerative processes in PD; however, the key molecular signaling mechanisms underlying microglial activation are not entirely clear. Herein, we identified a novel role for the non-receptor tyrosine kinase Fyn in regulating neuroinflammatory responses in microglia. Our data clearly suggest that the Fyn-PKCδ signaling axis acts as a major upstream signaling mediator of the sustained neuroinflammatory processes in cell culture and animal models of PD. Our finding has important clinical significance to PD because it identifies Fyn as a potential translational target for intervention of progressive neurodegenerative processes in PD.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 07/2015; 35(27):10058-77. DOI:10.1523/JNEUROSCI.0302-15.2015 · 6.34 Impact Factor
  • Adhithiya Charli · Huajun Jin · Vellareddy Anantharam · Arthi Kanthasamy · Anumantha G Kanthasamy ·
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    ABSTRACT: Tebufenpyrad and pyridaben are two agro-chemically important acaricides that function like the known mitochondrial toxicant rotenone. Although these two compounds have been commonly used to kill populations of mites and ticks in commercial greenhouses, their neurotoxic profiles remain largely unknown. Therefore, we investigated the effects of these two pesticides on mitochondrial structure and function in an in vitro cell culture model using the Seahorse bioanalyzer and confocal fluorescence imaging. The effects were compared with rotenone. Exposing rat dopaminergic neuronal cells (N27 cells) to tebufenpyrad and pyridaben for 3h induced dose-dependent cell death with an EC50 of 3.98μM and 3.77μM, respectively. Also, tebufenpyrad and pyridaben (3μM) exposure induced reactive oxygen species (ROS) generation and m-aconitase damage, suggesting that the pesticide toxicity is associated with oxidative damage. Morphometric image analysis with the MitoTracker red fluorescent probe indicated that tebufenpyrad and pyridaben, as well as rotenone, caused abnormalities in mitochondrial morphology, including reduced mitochondrial length and circularity. Functional bioenergetic experiments using the Seahorse XF96 analyzer revealed that tebufenpyrad and pyridaben very rapidly suppressed the basal mitochondrial oxygen consumption rate similar to that of rotenone. Further analysis of bioenergetic curves also revealed dose-dependent decreases in ATP-linked respiration and respiratory capacity. The luminescence-based ATP measurement further confirmed that pesticide-induced mitochondrial inhibition of respiration is accompanied by the loss of cellular ATP. Collectively, our results suggest that exposure to the pesticides tebufenpyrad and pyridaben induces neurotoxicity by rapidly initiating mitochondrial dysfunction and oxidative damage in dopaminergic neuronal cells. Our findings also reveal that monitoring the kinetics of mitochondrial respiration with Seahorse could be used as an early neurotoxicological high-throughput index for assessing the risk that pesticides pose to the dopaminergic neuronal system. Copyright © 2015. Published by Elsevier B.V.
    NeuroToxicology 06/2015; DOI:10.1016/j.neuro.2015.06.007 · 3.38 Impact Factor
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    ABSTRACT: Parkinson's disease (PD) is the second most common progressive neu-rodegenerative disorder that is characterized by the progressive loss of substan-tia nigral dopaminergic neurons resulting in the pronounced depletion of striatal DA levels which subsequently leads to the expression of cardinal features of PD including tremor, bradykinesia, rigidity and postural instability. The mechanisms underlying the selective loss of dopaminergic neurons remain poorly understood; however, studies conducted in post mortem PD brains and experimental PD models have implicated oxidative stress and mitochondrial dysfunction in the mechanism of dopaminergic neurodegeneration. In recent years, the etiology of several neurodegenerative diseases including PD has been linked to low dose and chronic exposure to a variety of agrochemicals including paraquat, rotenone and dieldrin. Here we discuss how several of these pesticides share common mechanistic events, including oxidative stress, mitochondrial impairment/complex I inhibition, abnormal protein aggregation and post translational modifications (PTMs) of proteins including α-synuclein, as well as dopaminergic cell death. Furthermore, intersecting and parallel effects of environmental neurotoxicants on protein clearance mechanisms and mitochondrial function are addressed and hence provide novel insights that might be beneficial in the development of targeted therapies for PD.
    Toxicity and Autophagy in Neurodegenerative Disorders, Edited by José M. Fuentes, 05/2015: chapter Agrochemicals-Induced Dopaminergic Neurotoxicity: Role of Mitochondria-Mediated Oxidative Stress and Protein Clearance Mechanisms: pages 171-204; Springer International Publishing., ISBN: 978-3-319-13939-5

  • Neurotoxicology and Teratology 05/2015; 49:109. DOI:10.1016/ · 2.76 Impact Factor
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    ABSTRACT: Numerous studies have suggested a positive association between pesticide exposure and the risk of developing Parkinson’s disease (PD). Previous studies indicated that dichlorvos (DCV), an organophosphate (OP) pesticide induced nigrostriatal dopaminergic neuronal death; however, the molecular mechanisms underlying DCV-induce cell death remains elusive. Using multiple approaches including, subcellular fractionation, immunofluorescence analysis, enzymatic assays, gene silencing technology we show that Abelson murine leukemia (c-Abl) tyrosine kinase is linked to DCV-induced dopaminergic cell death. Exposure of N27 mesencephalic dopaminergic neuronal cells to DCV, induced cell death via the upregulation of c-Abl, proteolytic cleavage and phosphorylation of PKC, mitochondrial dysfunction, and apoptotic events involving Bax upregulation, activation of caspase-9 and 3; and DNA fragmentation. Furthermore, a concomitant impairment in mitochondrial biogenesis (decreased TFAM & PGC1 levels); and protein clearance mechanisms, as assessed by the accumulation of ubiquitinated aggregates and enhancement of autophagic markers (LC3IIB & BECN-1) were found to precede DCV-induced cell death. In order to examine the role of c-Abl in DCV-induced cell death we used Dasatinib, a pharmacological inhibitor of c-Abl and gene silencing of c-Abl via siRNA. Both strategies ameliorated DCV-induced apoptotic cell death by attenuating the afore mentioned deficits namely mitochondrial dysfunction, protein clearance mechanisms, and mitochondrial biogenesis. Importantly, an increase in the levels of c-Abl and autophagy related markers were evidenced in the substantia nigra of MPTP treated mice. Our findings identify c-Abl tyrosine kinase as a novel upstream regulator of mitochondrial homeostasis and that phosphorylation of PKCδ by c-Abl is a key posttranslational modification that is pivotal for the deregulation of mitochondrial biogenesis and protein clearance machinery, thereby leading to the induction of cell death in N27 cells exposed to DCV (Supported by NIHES1058667).
    Society of Toxicology 2015, San Diego, CA; 03/2015
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    ABSTRACT: Interest in nanoneuromedicine has grown rapidly due to the immediate need for improved biomarkers and therapies for psychiatric, developmental, traumatic, inflammatory, infectious and degenerative nervous system disorders. These, in whole or in part, are a significant societal burden due to growth in numbers of affected people and in disease severity. Lost productivity of the patient and his or her caregiver, and the emotional and financial burden cannot be overstated. The need for improved health care, treatment and diagnostics are immediate. A means to such an end is nanotechnology. Indeed, recent developments of health-care enabling nanotechnologies and nanomedicines range from biomarker discovery including neuroimaging to therapeutic applications for degenerative, inflammatory and infectious disorders of the nervous system. This review focuses on the current and future potential of the field to positively affect clinical outcomes. Copyright © 2015. Published by Elsevier Inc.
    Nanomedicine Nanotechnology Biology and Medicine 01/2015; 9(3). DOI:10.1016/j.nano.2014.12.014 · 6.16 Impact Factor
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    ABSTRACT: Parkinson's diseaseParkinson's disease (PDPD ) is mainly characterized by a progressive degeneration of dopaminergicdopaminergic neuronsdopaminergic neurons in the substantia nigrasubstantia nigra resulting in chronic deficits in motor functions. Administration of the neurotoxinneurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTPMPTP ) produces PD symptoms and recapitulates the main features of PD in human and animal modelsanimal models . MPTP is converted to 1-methyl-4-phenylpyridine1-methyl-4-phenylpyridine (MPP(+) MPP(+) ), which is the active toxic compound that selectively destroys dopaminergic neurons. Here, we describe methods and protocols to evaluate MPTP/MPP(+)-induced dopaminergic neurodegenerationneurodegeneration in both murine primary mesencephalicmesencephalic culturesprimary mesencephalic cultures and animal models. The ability of MPTP/MPP(+) to cause dopaminergic neuronal cell deathcell death is assessed by immunostaining of tyrosine hydroxylasetyrosine hydroxylase (THTH ).
    Methods in molecular biology (Clifton, N.J.) 01/2015; 1254:239-52. DOI:10.1007/978-1-4939-2152-2_18 · 1.29 Impact Factor
  • H. Jin · D.S. Harischandra · C. Choi · D. Martin · V. Anantharam · A. Kanthasamy · A.G. Kanthasamy ·

    Issues in Toxicology 01/2015; 2015(22):574-603.
  • Yiwen Meng · Ravi Hadimani · Vellareddy Anantharam · Anumantha Kanthasamy · David Jiles ·

  • Yiwen Meng · Ravi Hadimani · Vellareddy Anantharam · Anumantha Kanthasamy · David Jiles ·

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    ABSTRACT: Prion diseases are a class of fatal neurodegenerative diseases caused by misfolding of the endogenous prion protein (PrPC) induced by exposure to the pathogenic conformational isomer of PrP (PrPSc) or by heritable mutation of PrPC. Although the exact role of the protein has yet to be solved, considerable evidence reveals prion protein to be a metalloprotein harboring divalent metal-binding sites for various cations such as copper, manganese, zinc, and nickel. Despite low-affinity binding to prion protein, when manganese interacts with prion, it can alter the development and transmission of prion disease. In this chapter, the role of metals in the pathogenesis of prion disease will be discussed. Particular emphasis will be placed on the link between manganese and PrPC.
    01/2015: pages 574-603; The Royal Society of Chemistry., ISBN: 9781849739436
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    Bonto Faburay · Dongseob Tark · Anumantha G Kanthasamy · Juergen A Richt ·
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    ABSTRACT: Protein misfolding cyclic amplification (PMCA) is an in vitro simulation of prion replication, which relies on the use of normal brain homogenate derived from host species as substrate for the specific amplification of abnormal prion protein, PrPSc. Studies showed that recombinant cellular PrP, PrPC, expressed in Escherichia coli lacks N-glycosylation and an glycophosphatidyl inositol anchor (GPI) and therefore may not be the most suitable substrate in seeded PMCA reactions to recapitulate prion conversion in vitro. In this study, we expressed 2 PRNP genotypes of sheep, V(136)L(141)R(154)Q(171) and A(136)F(141)R(154)Q(171), and one genotype of white-tailed deer (Q(95)G(96), X-132,Y-216) using the baculovirus expression system and evaluated their suitability as substrates in seeded-PMCA. It has been reported that host-encoded mammalian RNA molecules and divalent cations play a role in the pathogenesis of prion diseases, and RNA molecules have also been shown to improve the sensitivity of PMCA assays. Therefore, we also assessed the effect of co-factors, such as prion-specific mRNA molecules and a divalent cation, manganese, on protein conversion. Here, we report that baculovirus-expressed recombinant PrPC shows a glycoform and GPI-anchor profile similar to mammalian brain-derived PrPC and supports amplification of PrPSc and PrPCWD derived from prion-affected animals in a single round of seeded PMCA in the absence of exogenous co-factors. Addition of species-specific in vitro transcribed PrP mRNA molecules stimulated the conversion efficiency resulting in increased PrPSc or PrPCWD production. Addition of 2 to 20M of manganese chloride (MnCl2) to unseeded PMCA resulted in conversion of recombinant PrPC to protease-resistant PrP. Collectively, we demonstrate, for the first time, that baculovirus expressed sheep and deer PrP can serve as a substrate in protein misfolding cyclic amplification for sheep and deer prions in the absence of additional exogenous co-factors.
    Prion 12/2014; 8(6). DOI:10.4161/19336896.2014.983753 · 2.24 Impact Factor
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    ABSTRACT: The pathological role of α-synuclein (α-Syn) aggregation in neurodegeneration is well recognized, but the physiological function of normal α-Syn remains unknown. As α-Syn protein contains multiple divalent metal binding sites, herein we conducted a comprehensive characterization of the role of α-Syn in manganese-induced dopaminergic neurotoxicity. We established transgenic N27 dopaminergic neuronal cells by stably expressing human wild-type α-Syn at normal physiological levels. α-Syn-expressing dopaminergic cells significantly attenuated Mn-induced neurotoxicity for 24-h exposures relative to vector control cells. To further explore cellular mechanisms, we studied the mitochondria-dependent apoptotic pathway. Analysis of a key mitochondrial apoptotic initiator, cytochrome c, revealed that α-Syn significantly reduces the Mn-induced cytochrome c release into cytosol. The downstream caspase cascade, involving caspase-9 and caspase-3 activation, during Mn exposure was also largely attenuated in Mn-treated α-Syn cells in a time-dependent manner. α-Syn cells also showed a dramatic reduction in the Mn-induced proteolytic activation of the pro-apoptotic kinase PKCδ. The generation of Mn-induced reactive oxygen species (ROS) did not differ between α-Syn and vector control cells, indicating that α-Syn exerts its protective effect independent of altering ROS generation. Inductively coupled plasma-mass spectrometry (ICP-MS) revealed no significant differences in intracellular Mn levels between treated vector and α-Syn cells. Notably, the expression of wild-type α-Syn in primary mesencephalic cells also rescued cells from Mn-induced neurotoxicity. However, prolonged exposure to Mn promoted protein aggregation in α-Syn-expressing cells. Collectively, these results demonstrate that wild-type α-Syn exhibits neuroprotective effects against Mn-induced neurotoxicity during the early stages of exposure in a dopaminergic neuronal model of PD.
    Toxicological Sciences 11/2014; 143(3). DOI:10.1093/toxsci/kfu247 · 3.85 Impact Factor
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    ABSTRACT: The oxidative stress-sensitive protein kinase Cδ (PKCδ) has been implicated in dopaminergic neuronal cell death. However, little is known about the epigenetic mechanisms regulating PKCδ expression in neurons. Here, we report a novel mechanism by which the PKCδ gene can be regulated by histone acetylation. Treatment with histone deacetylase inhibitor (HDACi) sodium butyrate (NaBu) induced PKCδ expression in cultured neurons, brain slices, and animal models. Several other HDACi also mimicked NaBu. The chromatin immunoprecipitation analysis revealed that hyperacetylation of histone H4 by NaBu is associated with the PKCδ promoter. Deletion analysis of PKCδ promoter mapped the NaBu-responsive element to an 81-bp minimal promoter region. Detailed mutagenesis studies within this region revealed that four GC boxes conferred hyperacetylation-induced PKCδ promoter activation. Cotransfection experiments and Sp inhibitors studies demonstrated that Sp1, Sp3 and Sp4 regulated NaBu-induced PKCδ upregulation. However, NaBu did not alter the DNA binding activities of Sp proteins or their expression. Interestingly, a one-hybrid analysis revealed that NaBu enhanced transcriptional activity of Sp1/Sp3. Overexpression of p300/CBP potentiated the NaBu-mediated transactivation potential of Sp1/Sp3, whereas expressing several HDACs attenuated this effect, suggesting that p300/CBP and HDACs act as co-activators or co-repressors in histone acetylation-induced PKCδ upregulation. Finally, using genetic and pharmacological approaches, we showed that NaBu upregulation of PKCδ sensitizes neurons to cell death in a human dopaminergic cell model and brain slice cultures. Together, these results indicate that histone acetylation regulates PKCδ expression to augment nigrostriatal dopaminergic cell death, which could contribute to the progressive neuropathogenesis of Parkinson's disease.
    Journal of Biological Chemistry 10/2014; 289(50). DOI:10.1074/jbc.M114.576702 · 4.57 Impact Factor
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    ABSTRACT: Recently, we demonstrated that dimeric apocynin prevented loss of motor function in the leucine-rich repeat kinase 2 (LRRK2(R1441G)) transgenic (tg) mouse (treated with 200mg/kg, three times per week) [B.P. Dranka et al., Neurosci. Lett. 549 (2013) 57-62]. Here we extend those studies by treating LRRK2(R1441G) mice with an orally-available, mitochondrially-targeted apocynin derivative. We hypothesized that the increased mitochondrial permeability of Mito-apocynin, due to the triphenylphosphonium moiety, would allow improvement of Parkinson's disease (PD) symptoms at lower doses than those required for diapocynin. Tests of motor coordination (pole test, Rotor-Rod) revealed a significant deficit in coordinated motor function in LRRK2(R1441G) mice by 15 months of age. Decreased performance on the pole test and Rotor-Rod in the LRRK2(R1441G) mice was prevented with Mito-apocynin treatment (3mg/kg, three times per week). Decreased olfactory function is an early indication of PD in human patients. LRRK2(R1441G) tg mice displayed deficits in sense of smell in both the hidden treat test, and a radial arm maze test. Interestingly, treatment with Mito-apocynin prevented this hyposmia, and animals retained normal ability to identify either a scented treat or a food pellet as well as wild type littermates. Together, these data demonstrate that the mitochondria-targeted apocynin analog is effective in preventing early PD-like symptoms in the LRRK2(R1441G) mouse model.
    Free Radical Biology and Medicine 09/2014; 65. DOI:10.1016/j.neulet.2014.09.042 · 5.74 Impact Factor
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    ABSTRACT: Oxidative stress is a major pathophysiological mediator of degenerative processes in many neurodegenerative diseases including Parkinson's disease (PD). Aberrant cell signaling governed by protein phosphorylation has been linked to oxidative damage of dopaminergic neurons in PD. Although several studies have associated activation of certain protein kinases with apoptotic cell death in PD, very little is known about protein kinase regulation of cell survival and protection against oxidative damage and degeneration in dopaminergic neurons. Here, we characterized the PKD1-mediated protective pathway against oxidative damage in cell culture models of PD. Dopaminergic neurotoxicant 6-hydroxy dopamine (6-OHDA) was used to induce oxidative stress in the N27 dopaminergic cell model and in primary mesencephalic neurons. Our results indicated that 6-OHDA induced the PKD1 activation loop (PKD1S744/S748) phosphorylation during early stages of oxidative stress and that PKD1 activation preceded cell death. We also found that 6-OHDA rapidly increased phosphorylation of the C-terminal S916 in PKD1, which is required for PKD1 activation loop (PKD1S744/748) phosphorylation. Interestingly, negative modulation of PKD1 activation by RNAi knockdown or by the pharmacological inhibition of PKD1 by kbNB-14270 augmented 6-OHDA-induced apoptosis, while positive modulation of PKD1 by the overexpression of full length PKD1 (PKD1WT) or constitutively active PKD1 (PKD1S744E/S748E) attenuated 6-OHDA-induced apoptosis, suggesting an anti-apoptotic role for PKD1 during oxidative neuronal injury. Collectively, our results demonstrate that PKD1 signaling plays a cell survival role during early stages of oxidative stress in dopaminergic neurons and therefore, positive modulation of the PKD1-mediated signal transduction pathway can provide a novel neuroprotective strategy against PD.
    PLoS ONE 05/2014; 9(5):e96947. DOI:10.1371/journal.pone.0096947 · 3.23 Impact Factor
  • Qi Xu · Anumantha Kanthasamy · HuaJun Jin · Manju Reddy ·

    The FASEB Journal 04/2014; 28(1). · 5.04 Impact Factor
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    ABSTRACT: Acetylation and deacetylation of histones has been shown to be a critical regulator of gene transcription and chromatin remodeling. We have previously demonstrated that NF-κB activation is critically linked to trichostatin A (TSA)-induced apoptotic cell death in N27 dopaminergic cells. However, the influence of protein kinase c delta (PKCδ), a redox sensitive kinase, on histone hyperacetylation and its impact on dopaminergic neuronal survival remains to be established. Therefore in the present study we sought to investigate the link between PKCδ dependent oxidative stress and histone hyperacetylation. Herein we show that exposure of N27 cells to TSA for various time periods (3-12h) induced a time dependent increase in Bax activation, dissipation of MMP, caspase activation, NADPH oxidase activation, and GSH depletion. These changes preceded the drug induced apoptotic cell death. Intriguingly, a concomitant activation of PKC delta that paralleled histone hyperacetylation was evidenced in TSA treated cells. Moreover, TSA- induced increase in the expression of transcriptional regulators, such as p53, STAT1, and NF-κB, positively correlated with increased expression of pro-apoptotic factors. Notably, down regulation of PKCδ levels via ectopic overexpression of a caspase cleavage mutant of PKCδ (D327A) or small interference RNA-mediated gene silencing attenuated mitochondria mediated oxidative cell signaling events, transcription factor activation, histone hyperacetylation, and apoptotic cell death. Collectively, these findings identify PKCδ as a key regulator of TSA-induced hyperacetylation of histones and suggest that oxidative stress mediated proteolytic activation of PKCδ contributes to dopaminergic neuronal demise at least in part via deregulation of cellular epigenetic mechanisms (Supported by NIH ES10586 and NS065167).
    Society of Toxicology 2014, Phoenix, AZ; 03/2014

Publication Stats

5k Citations
554.44 Total Impact Points


  • 2002-2015
    • Iowa State University
      • Department of Biomedical Sciences
      Ames, Iowa, United States
  • 2012
    • University of Michigan
      • Life Sciences Institute
      Ann Arbor, MI, United States
  • 2008
    • CUNY Graduate Center
      New York City, New York, United States
  • 2000
    • Long Beach Memorial Medical Center
      Long Beach, California, United States
  • 1996-1999
    • University of California, Irvine
      • Division of Neurology
      Irvine, California, United States
  • 1991-1997
    • Purdue University
      • Department of Medicinal Chemistry and Molecular Pharmacology (MCMP)
      West Lafayette, Indiana, United States