Publications by authors named "Radhika Chadha"

9 Publications

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mTOR kinase activity disrupts a phosphorylation signaling network in schizophrenia brain.

Mol Psychiatry 2021 May 14. Epub 2021 May 14.

Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL, USA.

The AKT-mTOR signaling transduction pathway plays an important role in neurodevelopment and synaptic plasticity. mTOR is a serine/threonine kinase that modulates signals from multiple neurotransmitters and phosphorylates specific proteins to regulate protein synthesis and cytoskeletal organization. There is substantial evidence demonstrating abnormalities in AKT expression and activity in different schizophrenia (SZ) models. However, direct evidence for dysregulated mTOR kinase activity and its consequences on downstream effector proteins in SZ pathophysiology is lacking. Recently, we reported reduced phosphorylation of mTOR at an activating site and abnormal mTOR complex formation in the SZ dorsolateral prefrontal cortex (DLPFC). Here, we expand on our hypothesis of disrupted mTOR signaling in the SZ brain and studied the expression and activity of downstream effector proteins of mTOR complexes and the kinase activity profiles of SZ subjects. We found that S6RP phosphorylation, downstream of mTOR complex I, is reduced, whereas PKCα phosphorylation, downstream of mTOR complex II, is increased in SZ DLPFC. In rats chronically treated with haloperidol, we showed that S6RP phosphorylation is increased in the rat frontal cortex, suggesting a potential novel mechanism of action for antipsychotics. We also demonstrated key differences in kinase signaling networks between SZ and comparison subjects for both males and females using kinome peptide arrays. We further investigated the role of mTOR kinase activity by inhibiting it with rapamycin in postmortem tissue and compared the impact of mTOR inhibition in SZ and comparison subjects using kinome arrays. We found that SZ subjects are globally more sensitive to rapamycin treatment and AMP-activated protein kinase (AMPK) contributes to this differential kinase activity. Together, our findings provide new insights into the role of mTOR as a master regulator of kinase activity in SZ and suggest potential targets for therapeutic intervention.
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http://dx.doi.org/10.1038/s41380-021-01135-9DOI Listing
May 2021

Mitophagy impairment in neurodegenerative diseases: Pathogenesis and therapeutic interventions.

Mitochondrion 2021 03 19;57:270-293. Epub 2021 Jan 19.

Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, USA.

Neurons are specialized cells, requiring a lot of energy for its proper functioning. Mitochondria are the key cellular organelles and produce most of the energy in the form of ATP, required for all the crucial functions of neurons. Hence, the regulation of mitochondrial biogenesis and quality control is important for maintaining neuronal health. As a part of mitochondrial quality control, the aged and damaged mitochondria are removed through a selective mode of autophagy called mitophagy. However, in different pathological conditions, this process is impaired in neuronal cells and lead to a variety of neurodegenerative disease (NDD). Various studies indicate that specific protein aggregates, the characteristics of different NDDs, affect this process of mitophagy, adding to the severity and progression of diseases. Though, the detailed process of this association is yet to be explored. In light of the significant role of impaired mitophagy in NDDs, further studies have also investigated a large number of therapeutic strategies to target mitophagy in these diseases. Our current review summarizes the abnormalities in different mitophagy pathways and their association with different NDDs. We have also elaborated upon various novel therapeutic strategies and their limitations to enhance mitophagy in NDDs that may help in the management of symptoms and increasing the life expectancy of NDD patients. Thus, our study provides an overview of mitophagy in NDDs and emphasizes the need to elucidate the mechanism of impaired mitophagy prevalent across different NDDs in future research. This will help designing better treatment options with high efficacy and specificity.
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http://dx.doi.org/10.1016/j.mito.2021.01.001DOI Listing
March 2021

Downregulated AKT-mTOR signaling pathway proteins in dorsolateral prefrontal cortex in Schizophrenia.

Neuropsychopharmacology 2020 05 17;45(6):1059-1067. Epub 2020 Jan 17.

Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, 1719 6th Avenue South, Birmingham, AL, 35294-0021, USA.

Abnormal neurotransmission is central to schizophrenia (SZ). Alterations across multiple neurotransmitter systems in SZ suggest that this illness may be associated with dysregulation of core intracellular processes such as signaling pathways that underlie the regulation and integration of these systems. The AKT-mTOR signaling cascade has been implicated in SZ by gene association, postmortem brain and animal studies. AKT and mTOR are serine/threonine kinases which play important roles in cell growth, proliferation, survival, and differentiation. Both AKT and mTOR require phosphorylation at specific sites for their complete activation. mTOR forms two functionally distinct multiprotein complexes, mTOR Complex 1 (mTORC1) and Complex 2 (mTORC2). mTORC1 mediates ribosome biogenesis, protein translation, and autophagy, whereas mTORC2 contributes to actin dynamics. Altered protein synthesis and actin dynamics can lead to an abnormal neuronal morphology resulting in deficits in learning and memory. Currently, there is a lack of direct evidence to support the hypothesis of disrupted mTOR signaling in SZ, and we have addressed this by characterizing this signaling pathway in SZ brain. We found a reduction in AKT and mTOR protein expression and/or phosphorylation state in dorsolateral prefrontal cortex (DLPFC) from 22 pairs of SZ and matched comparison subjects. We also found reduced protein expression of GβL, a subunit protein common to both mTOR complexes. We further investigated mTOR complex-specific subunit composition and phosphorylation state, and found abnormal mTOR expression in both complexes in SZ DLPFC. These findings provide evidence that proteins associated with the AKT-mTOR signaling cascade are downregulated in SZ DLPFC.
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http://dx.doi.org/10.1038/s41386-020-0614-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7162985PMC
May 2020

The HBx gene of hepatitis B virus can influence hepatic microenvironment via exosomes by transferring its mRNA and protein.

Virus Res 2017 08 25;240:166-174. Epub 2017 Aug 25.

Virology Group, International Centre for Genetic Engineering and Biotechnology, New Delhi, India. Electronic address:

The cellular secretory vesicles known as 'exosomes' have emerged as key player in intercellular transport and communication between different eukaryotic in order to maintain body homeostasis. Many pathogenic viruses utilize exosome pathway to efficiently transfer bioactive components from infected cells to naïve cells. Here, we show that HBx can tweak the exosome biogenesis machinery both by enhancing neutral sphingomyelinase2 activity as well as by interacting with exosomal biomarkers such as neutral sphingomyelinase2, CD9 and CD81. The nano particle tracking analysis revealed enhanced secretion of exosomes by the HBx-expressing cells while confocal studies confirmed the co-localization of HBx with CD9 and CD63. Importantly, we observed the encapsulation of HBx mRNA and protein in these exosomes besides some other qualitative changes. The exosomal cargo secreted by HBx-expressing cells had a profound effect on the recipient hepatic cells including creation of a milieu conducive for cellular-transformation. Thus, the present study unfolds a novel role of HBx in intercellular communication by facilitating horizontal transfer of viral gene products and other host factors via exosomes in order to support viral spread and pathogenesis.
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http://dx.doi.org/10.1016/j.virusres.2017.08.009DOI Listing
August 2017

Optimising organs for transplantation: is normothermic machine perfusion the answer?

Expert Rev Med Devices 2016 20;13(3):221-3. Epub 2016 Feb 20.

c Head of Transplantation, Consultant Transplant and Endocrine Surgeon , Leicester General Hospital , Leicester , UK.

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http://dx.doi.org/10.1586/17434440.2016.1146587DOI Listing
November 2016

The unique immunobiology of the skin: implications for tolerance of vascularized composite allografts.

Curr Opin Organ Transplant 2014 Dec;19(6):566-72

aUniversity of Oxford, Oxford, UK bTransplantation Biology Research Center cDivision of Plastic and Reconstructive Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA dDepartment of Plastic and Reconstructive Surgery Research, University of Manchester, Manchester, UK eDepartment of Biology, Emmanuel College, Boston, Massachusetts, USA.

Purpose Of Review: Vascularized composite allograft (VCA) transplantation restores function and form following major soft tissue and musculoskeletal injury. Lifelong immunosuppression is necessary for graft function and survival but acute skin-targeted rejection episodes remain common. We review recent advances in skin immunobiology, emphasizing findings in clinical and experimental VCAs. We also highlight advances in immunotherapy and tolerance protocols with implications for the prevention of VCA rejection, and ultimately, induction of clinically applicable strategies for VCA tolerance.

Recent Findings: There is now an increasing appreciation for the role of skin-specific mechanisms, including lymphoid neogenesis, in VCA rejection. In contrast, expression of the regulatory master-switch FOXP3 was demonstrated to be significantly upregulated in the skin of tolerant VCAs in large animal models compared with normal skin and rejecting controls.

Summary: Most VCA transplant centers continue to utilize antibody-mediated induction therapy and triple agent maintenance immunosuppression. Skin remains the primary target of rejection in VCAs, and current multicenter studies hope to elucidate the mechanisms involved. Proposed standardized procedures for skin biopsies, and diligent reporting of clinical data to the international registry, will be important to maximize the strength of these studies.
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http://dx.doi.org/10.1097/MOT.0000000000000136DOI Listing
December 2014

Analysis of reported SCO2 gene mutations affecting cytochrome c oxidase activity in various diseases.

Bioinformation 2014 30;10(6):329-33. Epub 2014 Jun 30.

Department of Biotechnology, Jaypee Institute of Information Technology, Noida.

A large number of mutations have been reported in SCO2 (synthesis of cytochrome c oxidase) gene in association with COX deficiency reported in different diseases such as cardioencephalomyopathy, cardiomyopathy and Leigh syndrome. However, very few of these mutations have been functionally analyzed.SCO2 gene encodes for an essential assembly factor for the formation of cytochrome c oxidase (COX). It is a nuclear encoded protein that helps in transfer of copper ions to COX. This study is an attempt to understand the possible effect of these mutations on the structure and function of SCO2 protein, by using different in silico tools. As per Human Gene Mutation Database, total 11 non synonymous variations have been reported in SCO2 gene. Among these 11 variations, only E140K and R171W are functionally proven to cause COX deficiency. They have been used as controls in this study. The remaining variations were further analyzed using ClustalW, SIFT, PolyPhen-2, GOR4, MuPro and Panther softwares. As compared to the results of the controls, most of these variations were predicted to affect the structure of SCO2 protein and hence, may cause COX dysfunction. Thus, we hypothesize that these variations have the potential to result in a disease phenotype and should be investigated by subsequent functional analyses. This will help in an appropriate diagnosis and management of the wide spectrum of COX deficiency diseases.
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http://dx.doi.org/10.6026/97320630010329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4110422PMC
August 2014

Th17: contributors to allograft rejection and a barrier to the induction of transplantation tolerance?

Transplantation 2011 May;91(9):939-45

T helper (Th) type 17 cells are a recently described CD4 T-cell subset that may contribute to allograft rejection and act as a barrier to the induction of transplant tolerance. This review examines the involvement of Th17 cells in transplant rejection, how immunosuppressive medication may affect their induction and maintenance and the potential plasticity of developing Th17 cells. It also addresses the complex interplay between the Th17 and regulatory T-cell developmental pathways and the susceptibility of Th17 cells to regulation. Despite accumulating evidence, the precise impact of Th17 cells on transplant rejection and the induction of tolerance require further clarification.
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http://dx.doi.org/10.1097/TP.0b013e3182126eebDOI Listing
May 2011

The impact of Th17 cells on transplant rejection and the induction of tolerance.

Curr Opin Organ Transplant 2010 Aug;15(4):456-61

Transplant Research Immunology Group, Nuffield Department of Surgery, University of Oxford, John Radcliffe Hospital, Oxford, UK.

Purpose Of Review: This review aims to provide an overview of the latest evidence for the involvement of Th17 cells in the rejection of solid organ allografts. It will also consider the implications of the relationship between the differentiation pathways of Th17 and regulatory T cells (Tregs), as well as their plasticity in the context of transplantation tolerance.

Recent Findings: In the absence of the Th1 lineage in vivo, Th17 cells are capable of rejecting cardiac allografts, showing the capacity of Th17 cells to cause allograft rejection, at least in experimental models. Th17 cells are relatively unsusceptible to suppression by Tregs, although this may be context dependent. Furthermore, addition of inflammatory signals to a Treg-inducing environment leads to Th17 development and established Tregs can be converted to Th17 cells under inflammatory conditions.

Summary: The capacity of Th17 cells to cause allograft rejection is becoming increasingly clear. However, the role and contribution of Th17 cells in allograft rejection in the presence of the full orchestra of T helper cells remains elusive. The apparent resistance of Th17 to be suppressed by Tregs may pose a hurdle for effective immunosuppression and tolerance inducing protocols. Furthermore, the close developmental pathways of Th17 and Tregs and the ability of Tregs to convert into Th17 cells in the presence of inflammatory signals may impede the establishment of specific unresponsiveness to donor alloantigens in vivo.
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http://dx.doi.org/10.1097/MOT.0b013e32833b9bfbDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3095085PMC
August 2010