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Article ; Online: Gene therapy delivering a paraoxonase 1 variant offers long-term prophylactic protection against nerve agents in mice.

Betapudi, Venkaiah / Goswami, Reena / Silayeva, Liliya / Doctor, Deborah M / Chilukuri, Nageswararao

2020 Volume 12, Issue 527

Abstract: Chemical warfare nerve agents are organophosphorus chemical compounds that induce cholinergic crisis, leaving little or no time for medical intervention to prevent death. The current chemical treatment regimen may prevent death but does not prevent ... ...

Abstract	Chemical warfare nerve agents are organophosphorus chemical compounds that induce cholinergic crisis, leaving little or no time for medical intervention to prevent death. The current chemical treatment regimen may prevent death but does not prevent postexposure complications such as brain damage and permanent behavioral abnormalities. In the present study, we have demonstrated an adeno-associated virus 8 (AAV8)-mediated paraoxonase 1 variant IF-11 (PON1-IF11) gene therapy that offers asymptomatic prophylactic protection to mice against multiple lethal doses of G-type chemical warfare nerve agents, namely, tabun, sarin, cyclosarin, and soman, for up to 5 months in mice. A single injection of liver-specific adeno-associated viral particles loaded with PON1-IF11 gene resulted in expression and secretion of recombinant PON1-IF11 in milligram quantities, which has the catalytic power to break down G-type chemical warfare nerve agents into biologically inactive products in vitro and in vivo in rodents. Mice containing milligram concentrations of recombinant PON1-IF11 in their blood displayed no clinical signs of toxicity, as judged by their hematological parameters and serum chemistry profiles. Our study unfolds avenues to develop a one-time application of gene therapy to express a near-natural and circulating therapeutic PON1-IF11 protein that can potentially protect humans against G-type chemical warfare nerve agents for several weeks to months.
MeSH term(s)	Animals ; Aryldialkylphosphatase/genetics ; Aryldialkylphosphatase/metabolism ; Genetic Therapy/methods ; Humans ; Mice ; Nerve Agents/adverse effects
Chemical Substances	Nerve Agents ; Aryldialkylphosphatase (EC 3.1.8.1) ; PON1 protein, mouse (EC 3.1.8.1)
Language	English
Publishing date	2020-01-21
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2518854-9
ISSN	1946-6242 ; 1946-6234
ISSN (online)	1946-6242
ISSN	1946-6234
DOI	10.1126/scitranslmed.aay0356
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Article: Gene Therapy Leaves a Vicious Cycle.

Goswami, Reena / Subramanian, Gayatri / Silayeva, Liliya / Newkirk, Isabelle / Doctor, Deborah / Chawla, Karan / Chattopadhyay, Saurabh / Chandra, Dhyan / Chilukuri, Nageswararao / Betapudi, Venkaiah

Frontiers in oncology

2019 Volume 9, Page(s) 297

Abstract: The human genetic code encrypted in thousands of genes holds the secret for synthesis of proteins that drive all biological processes necessary for normal life and death. Though the genetic ciphering remains unchanged through generations, some genes get ... ...

Abstract	The human genetic code encrypted in thousands of genes holds the secret for synthesis of proteins that drive all biological processes necessary for normal life and death. Though the genetic ciphering remains unchanged through generations, some genes get disrupted, deleted and or mutated, manifesting diseases, and or disorders. Current treatment options-chemotherapy, protein therapy, radiotherapy, and surgery available for no more than 500 diseases-neither cure nor prevent genetic errors but often cause many side effects. However, gene therapy, colloquially called "living drug," provides a one-time treatment option by rewriting or fixing errors in the natural genetic ciphering. Since gene therapy is predominantly a viral vector-based medicine, it has met with a fair bit of skepticism from both the science fraternity and patients. Now, thanks to advancements in gene editing and recombinant viral vector development, the interest of clinicians and pharmaceutical industries has been rekindled. With the advent of more than 12 different gene therapy drugs for curing cancer, blindness, immune, and neuronal disorders, this emerging experimental medicine has yet again come in the limelight. The present review article delves into the popular viral vectors used in gene therapy, advances, challenges, and perspectives.
Language	English
Publishing date	2019-04-24
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2649216-7
ISSN	2234-943X
ISSN	2234-943X
DOI	10.3389/fonc.2019.00297
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Article ; Online: Benzodiazepine treatment induces subtype-specific changes in GABA(A) receptor trafficking and decreases synaptic inhibition.

Jacob, Tija C / Michels, Guido / Silayeva, Liliya / Haydon, Julia / Succol, Francesca / Moss, Stephen J

Proceedings of the National Academy of Sciences of the United States of America

2012 Volume 109, Issue 45, Page(s) 18595–18600

Abstract: Benzodiazepines potentiate γ-aminobutyric acid type A receptor (GABA(A)R) activity and are widely prescribed to treat anxiety, insomnia, and seizure disorders. Unfortunately, clinical use of benzodiazepines (BZs) is severely limited by tolerance. The ... ...

Abstract	Benzodiazepines potentiate γ-aminobutyric acid type A receptor (GABA(A)R) activity and are widely prescribed to treat anxiety, insomnia, and seizure disorders. Unfortunately, clinical use of benzodiazepines (BZs) is severely limited by tolerance. The mechanisms leading to BZ tolerance are unknown. BZs bind at the interface between an α and γ subunit of GABA(A)Rs, preferentially enhancing synaptic receptors largely composed of α(1-3, 5), β3, and γ2 subunits. Using confocal imaging and patch-clamp approaches, we show that treatment with the BZ flurazepam decreases GABA(A)R surface levels and the efficacy of neuronal inhibition in hippocampal neurons. A dramatic decrease in surface and total levels of α2 subunit-containing GABA(A)Rs occurred within 24 h of flurazepam treatment, whereas GABA(A)Rs incorporating α1 subunits showed little alteration. The GABA(A)R surface depletion could be reversed by treatment with the BZ antagonist Ro 15-1788. Coincident with decreased GABA(A)R surface levels, flurazepam treatment reduced miniature inhibitory postsynaptic current amplitude, which returned to control levels with acute Ro 15-1788 treatment. GABA(A)R endocytosis and insertion rates were unchanged by flurazepam treatment. Treatment with leupeptin restored flurazepam lowered receptor surface levels, strongly suggesting that flurazepam increases lysosomal degradation of GABA(A)Rs. Together, these data suggest that flurazepam exposure enhances degradation of α2 subunit-containing GABA(A)Rs after their removal from the plasma membrane, leading to a reduction in inhibitory synapse size and number along with a decrease in the efficacy of synaptic inhibition. These reported subtype-specific changes in GABA(A)R trafficking provide significant mechanistic insight into the initial neuroadaptive responses occurring with BZ treatment.
MeSH term(s)	Animals ; Benzodiazepines/pharmacology ; Binding Sites ; Cell Membrane/drug effects ; Cell Membrane/metabolism ; Endocytosis/drug effects ; Inhibitory Postsynaptic Potentials/drug effects ; Leupeptins/pharmacology ; Neural Inhibition/drug effects ; Neurons/drug effects ; Neurons/physiology ; Protein Subunits/metabolism ; Protein Transport/drug effects ; Rats ; Receptors, GABA-A/metabolism ; Synapses/drug effects ; Synapses/physiology
Chemical Substances	Leupeptins ; Protein Subunits ; Receptors, GABA-A ; Benzodiazepines (12794-10-4) ; leupeptin (J97339NR3V)
Language	English
Publishing date	2012-10-22
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.1204994109
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Article ; Online: Modulation of neuronal activity by phosphorylation of the K-Cl cotransporter KCC2.

Kahle, Kristopher T / Deeb, Tarek Z / Puskarjov, Martin / Silayeva, Liliya / Liang, Bo / Kaila, Kai / Moss, Stephen J

Trends in neurosciences

2013 Volume 36, Issue 12, Page(s) 726–737

Abstract: The K-Cl cotransporter KCC2 establishes the low intraneuronal Cl- levels required for the hyperpolarizing inhibitory postsynaptic potentials mediated by ionotropic γ-aminobutyric acid receptors (GABAARs) and glycine receptors (GlyRs). Decreased KCC2- ... ...

Abstract	The K-Cl cotransporter KCC2 establishes the low intraneuronal Cl- levels required for the hyperpolarizing inhibitory postsynaptic potentials mediated by ionotropic γ-aminobutyric acid receptors (GABAARs) and glycine receptors (GlyRs). Decreased KCC2-mediated Cl- extrusion and impaired hyperpolarizing GABAAR- and/or GlyR-mediated currents have been implicated in epilepsy, neuropathic pain, and spasticity. Recent evidence suggests that the intrinsic ion transport rate, cell surface stability, and plasmalemmal trafficking of KCC2 are rapidly and reversibly modulated by the (de)phosphorylation of critical serine, threonine, and tyrosine residues in the C terminus of this protein. Alterations in KCC2 phosphorylation have been associated with impaired KCC2 function in several neurological diseases. Targeting KCC2 phosphorylation directly or indirectly via upstream regulatory kinases might be a novel strategy to modulate GABA- and/or glycinergic signaling for therapeutic benefit.
MeSH term(s)	Animals ; Humans ; Models, Biological ; Nervous System Diseases/metabolism ; Nervous System Diseases/pathology ; Neurons/metabolism ; Phosphorylation ; Receptors, GABA ; Receptors, Glycine ; Signal Transduction/physiology ; Symporters/metabolism ; K Cl- Cotransporters
Chemical Substances	Receptors, GABA ; Receptors, Glycine ; Symporters
Language	English
Publishing date	2013-10-15
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	282488-7
ISSN	1878-108X ; 0378-5912 ; 0166-2236
ISSN (online)	1878-108X
ISSN	0378-5912 ; 0166-2236
DOI	10.1016/j.tins.2013.08.006
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Zs.A 1442: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: KCC2 activity is critical in limiting the onset and severity of status epilepticus.

Silayeva, Liliya / Deeb, Tarek Z / Hines, Rochelle M / Kelley, Matt R / Munoz, Michaelanne B / Lee, Henry H C / Brandon, Nicholas J / Dunlop, John / Maguire, Jaime / Davies, Paul A / Moss, Stephen J

Proceedings of the National Academy of Sciences of the United States of America

2015 Volume 112, Issue 11, Page(s) 3523–3528

Abstract: The K(+)/Cl(-) cotransporter (KCC2) allows adult neurons to maintain low intracellular Cl(-) levels, which are a prerequisite for efficient synaptic inhibition upon activation of γ-aminobutyric acid receptors. Deficits in KCC2 activity are implicated in ... ...

Abstract	The K(+)/Cl(-) cotransporter (KCC2) allows adult neurons to maintain low intracellular Cl(-) levels, which are a prerequisite for efficient synaptic inhibition upon activation of γ-aminobutyric acid receptors. Deficits in KCC2 activity are implicated in epileptogenesis, but how increased neuronal activity leads to transporter inactivation is ill defined. In vitro, the activity of KCC2 is potentiated via phosphorylation of serine 940 (S940). Here we have examined the role this putative regulatory process plays in determining KCC2 activity during status epilepticus (SE) using knockin mice in which S940 is mutated to an alanine (S940A). In wild-type mice, SE induced by kainate resulted in dephosphorylation of S940 and KCC2 internalization. S940A homozygotes were viable and exhibited comparable basal levels of KCC2 expression and activity relative to WT mice. However, exposure of S940A mice to kainate induced lethality within 30 min of kainate injection and subsequent entrance into SE. We assessed the effect of the S940A mutation in cultured hippocampal neurons to explore the mechanisms underlying this phenotype. Under basal conditions, the mutation had no effect on neuronal Cl(-) extrusion. However, a selective deficit in KCC2 activity was seen in S940A neurons upon transient exposure to glutamate. Significantly, whereas the effects of glutamate on KCC2 function could be ameliorated in WT neurons with agents that enhance S940 phosphorylation, this positive modulation was lost in S940A neurons. Collectively our results suggest that phosphorylation of S940 plays a critical role in potentiating KCC2 activity to limit the development of SE.
MeSH term(s)	Animals ; Chlorides/metabolism ; Endocytosis ; Gene Knock-In Techniques ; Glutamates/pharmacology ; Mice ; Mice, Neurologic Mutants ; Mutant Proteins/metabolism ; Mutation/genetics ; Phosphorylation ; Phosphoserine/metabolism ; Protein Phosphatase 1/antagonists & inhibitors ; Protein Phosphatase 1/metabolism ; Status Epilepticus/metabolism ; Status Epilepticus/pathology ; Symporters/genetics ; Symporters/metabolism ; gamma-Aminobutyric Acid/metabolism ; K Cl- Cotransporters
Chemical Substances	Chlorides ; Glutamates ; Mutant Proteins ; Symporters ; Phosphoserine (17885-08-4) ; gamma-Aminobutyric Acid (56-12-2) ; Protein Phosphatase 1 (EC 3.1.3.16)
Language	English
Publishing date	2015-03-02
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.1415126112
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Article ; Online: Selective inhibition of KCC2 leads to hyperexcitability and epileptiform discharges in hippocampal slices and in vivo.

Sivakumaran, Sudhir / Cardarelli, Ross A / Maguire, Jamie / Kelley, Matt R / Silayeva, Liliya / Morrow, Danielle H / Mukherjee, Jayanta / Moore, Yvonne E / Mather, Robert J / Duggan, Mark E / Brandon, Nicholas J / Dunlop, John / Zicha, Stephen / Moss, Stephen J / Deeb, Tarek Z

The Journal of neuroscience : the official journal of the Society for Neuroscience

2015 Volume 35, Issue 21, Page(s) 8291–8296

Abstract: GABA(A) receptors form Cl(-) permeable channels that mediate the majority of fast synaptic inhibition in the brain. The K(+)/Cl(-) cotransporter KCC2 is the main mechanism by which neurons establish low intracellular Cl(-) levels, which is thought to ... ...

Abstract	GABA(A) receptors form Cl(-) permeable channels that mediate the majority of fast synaptic inhibition in the brain. The K(+)/Cl(-) cotransporter KCC2 is the main mechanism by which neurons establish low intracellular Cl(-) levels, which is thought to enable GABAergic inhibitory control of neuronal activity. However, the widely used KCC2 inhibitor furosemide is nonselective with antiseizure efficacy in slices and in vivo, leading to a conflicting scheme of how KCC2 influences GABAergic control of neuronal synchronization. Here we used the selective KCC2 inhibitor VU0463271 [N-cyclopropyl-N-(4-methyl-2-thiazolyl)-2-[(6-phenyl-3-pyridazinyl)thio]acetamide] to investigate the influence of KCC2 function. Application of VU0463271 caused a reversible depolarizing shift in E(GABA) values and increased spiking of cultured hippocampal neurons. Application of VU0463271 to mouse hippocampal slices under low-Mg(2+) conditions induced unremitting recurrent epileptiform discharges. Finally, microinfusion of VU0463271 alone directly into the mouse dorsal hippocampus rapidly caused epileptiform discharges. Our findings indicated that KCC2 function was a critical inhibitory factor ex vivo and in vivo.
MeSH term(s)	Animals ; Animals, Newborn ; Cells, Cultured ; HEK293 Cells ; Hippocampus/drug effects ; Hippocampus/physiology ; Humans ; Membrane Potentials/drug effects ; Membrane Potentials/physiology ; Mice ; Mice, Inbred C57BL ; Organ Culture Techniques ; Rats ; Rats, Sprague-Dawley ; Sodium Potassium Chloride Symporter Inhibitors/pharmacology ; Symporters/antagonists & inhibitors ; Symporters/physiology ; Synaptic Transmission/drug effects ; Synaptic Transmission/physiology ; K Cl- Cotransporters
Chemical Substances	Sodium Potassium Chloride Symporter Inhibitors ; Symporters
Language	English
Publishing date	2015-05-27
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	604637-x
ISSN	1529-2401 ; 0270-6474
ISSN (online)	1529-2401
ISSN	0270-6474
DOI	10.1523/JNEUROSCI.5205-14.2015
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Zs.A 1668: Show issues

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Article ; Online: The small molecule CLP257 does not modify activity of the K

Nature medicine

2017 Volume 23, Issue 12, Page(s) 1394–1396

MeSH term(s)	Cell Line, Tumor ; Chlorides/metabolism ; HEK293 Cells ; Humans ; Patch-Clamp Techniques ; Protein Binding ; Receptors, GABA-A/drug effects ; Symporters/drug effects ; Symporters/metabolism ; Thallium/pharmacology ; Thiazolidines/pharmacology ; Transfection ; K Cl- Cotransporters
Chemical Substances	CLP257 ; Chlorides ; Receptors, GABA-A ; Symporters ; Thiazolidines ; Thallium (AD84R52XLF)
Language	English
Publishing date	2017-12-07
Publishing country	United States
Document type	Letter ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1220066-9
ISSN	1546-170X ; 1078-8956
ISSN (online)	1546-170X
ISSN	1078-8956
DOI	10.1038/nm.4442
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Zs.A 4212: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MG 39: Show issues

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Article ; Online: Genetically encoded impairment of neuronal KCC2 cotransporter function in human idiopathic generalized epilepsy.

EMBO reports

2014 Volume 15, Issue 7, Page(s) 766–774

Abstract: The KCC2 cotransporter establishes the low neuronal Cl(-) levels required for GABAA and glycine (Gly) receptor-mediated inhibition, and KCC2 deficiency in model organisms results in network hyperexcitability. However, no mutations in KCC2 have been ... ...

Abstract	The KCC2 cotransporter establishes the low neuronal Cl(-) levels required for GABAA and glycine (Gly) receptor-mediated inhibition, and KCC2 deficiency in model organisms results in network hyperexcitability. However, no mutations in KCC2 have been documented in human disease. Here, we report two non-synonymous functional variants in human KCC2, R952H and R1049C, exhibiting clear statistical association with idiopathic generalized epilepsy (IGE). These variants reside in conserved residues in the KCC2 cytoplasmic C-terminus, exhibit significantly impaired Cl(-)-extrusion capacities resulting in less hyperpolarized Gly equilibrium potentials (EG ly), and impair KCC2 stimulatory phosphorylation at serine 940, a key regulatory site. These data describe a novel KCC2 variant significantly associated with a human disease and suggest genetically encoded impairment of KCC2 functional regulation may be a risk factor for the development of human IGE.
MeSH term(s)	Action Potentials ; Alleles ; Animals ; Case-Control Studies ; Cell Line ; Chlorides/metabolism ; Epilepsy, Generalized/genetics ; Epilepsy, Generalized/metabolism ; Gene Frequency ; Genetic Variation ; Hippocampus/metabolism ; Humans ; Models, Molecular ; Mutation ; Phosphorylation ; Protein Conformation ; Protein Interaction Domains and Motifs ; Pyramidal Cells/metabolism ; Quebec ; Rats ; Symporters/chemistry ; Symporters/genetics ; Symporters/metabolism ; K Cl- Cotransporters
Chemical Substances	Chlorides ; Symporters
Language	English
Publishing date	2014-06-13
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2020896-0
ISSN	1469-3178 ; 1469-221X
ISSN (online)	1469-3178
ISSN	1469-221X
DOI	10.15252/embr.201438840
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Zs.A 5433: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article: Benzodiazepine treatment induces subtype-specific changes in GABAA receptor trafficking and decreases synaptic inhibition

Jacob, Tija C. / Michels, Guido / Silayeva, Liliya / Haydon, Julia / Succol, Francesca / Moss, Stephen J.

Proceedings of the National Academy of Sciences of the United States of America

Volume v. 109,, Issue no. 4

Abstract: Benzodiazepines potentiate γ-aminobutyric acid type A receptor (GABA AR) activity and are widely prescribed to treat anxiety, insomnia, and seizure disorders. Unfortunately, clinical use of benzodiazepines (BZs) is severely limited by tolerance. The ... ...

Abstract	Benzodiazepines potentiate γ-aminobutyric acid type A receptor (GABA AR) activity and are widely prescribed to treat anxiety, insomnia, and seizure disorders. Unfortunately, clinical use of benzodiazepines (BZs) is severely limited by tolerance. The mechanisms leading to BZ tolerance are unknown. BZs bind at the interface between an α and γ subunit of GABA ARs, preferentially enhancing synaptic receptors largely composed of α(1–3, 5), β3, and γ2 subunits. Using confocal imaging and patch-clamp approaches, we show that treatment with the BZ flurazepam decreases GABA AR surface levels and the efficacy of neuronal inhibition in hippocampal neurons. A dramatic decrease in surface and total levels of α2 subunit-containing GABA ARs occurred within 24 h of flurazepam treatment, whereas GABA ARs incorporating α1 subunits showed little alteration. The GABA AR surface depletion could be reversed by treatment with the BZ antagonist Ro 15-1788. Coincident with decreased GABA AR surface levels, flurazepam treatment reduced miniature inhibitory postsynaptic current amplitude, which returned to control levels with acute Ro 15-1788 treatment. GABA AR endocytosis and insertion rates were unchanged by flurazepam treatment. Treatment with leupeptin restored flurazepam lowered receptor surface levels, strongly suggesting that flurazepam increases lysosomal degradation of GABA ARs. Together, these data suggest that flurazepam exposure enhances degradation of α2 subunit-containing GABA ARs after their removal from the plasma membrane, leading to a reduction in inhibitory synapse size and number along with a decrease in the efficacy of synaptic inhibition. These reported subtype-specific changes in GABA AR trafficking provide significant mechanistic insight into the initial neuroadaptive responses occurring with BZ treatment.
Keywords	anxiety ; sleep disorders ; plasma membrane ; endocytosis ; benzodiazepines ; synapse ; receptors ; antagonists ; neurons ; gamma-aminobutyric acid ; image analysis
Language	English
Document type	Article
ISSN	0027-8424
Database	AGRIS - International Information System for the Agricultural Sciences and Technology

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