Publications by authors named "Rashmi Parihar"

21 Publications

  • Page 1 of 1

NMR based CSF metabolomics in tuberculous meningitis: correlation with clinical and MRI findings.

Metab Brain Dis 2022 Jan 14. Epub 2022 Jan 14.

Department of Neurology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, 226014, India.

We report the potential role of H Nuclear Magnetic Resonance (NMR) based metabolomics in tuberculous meningitis (TBM). We also correlate the significant metabolites with clinical-radiological parameters. Forty-three patients with TBM were included, and their severity of meningitis was graded as stages I to III, and patients with positive Mycobacterium tuberculosis or its nucleic acid was considered as definite TBM. H NMR-based metabolomic study was performed on (CSF) samples, and the significant metabolites compared to healthy controls were identified. Outcome at three months was defined as death, poor and good based on the modified Rankin Scale. These metabolites were compared between definite and probable groups of TBM, and also correlated with MRI findings. About 11 metabolites were found to be significant for distinguishing TBM from the controls. In TBM, lactate, glutamate, alanine, arginine, 2-hydroxyisobutyrate, formate, and cis-aconitate were upregulated, and glucose, fructose, glutamine, and myo-inositol were downregulated compared to the controls. For differentiating TBM from the controls, the AUC of the ROC curve generated using these significant metabolites was 0.99, with a 95% confidence interval from 0.96 to 1, demonstrating that these metabolites were able to classify cases with good sensitivity and specificity. Lactate concentration in CSF correlated with hemoglobin, CSF glucose, and infarction. The outcome did not correlate with metabolomics parameters. NMR-based CSF metabolomics have a potential role in differentiating TBM from the controls.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11011-021-00860-yDOI Listing
January 2022

Accelerated C detection by concentrating the NMR sample in a biphasic solvent system.

Analyst 2021 Oct 25;146(21):6582-6591. Epub 2021 Oct 25.

Centre of Biomedical Research (Formerly Centre of Biomedical Magnetic Resonance), SGPGIMS Campus, Raebareli Road, Lucknow, 226014, India.

CDCl is the most frequently used solvent for the NMR investigation of organic compounds. Busy chemistry labs need to investigate hundreds of compounds daily. While H NMR investigation takes a couple of minutes, recording C NMR spectra necessitates hours of signal averaging due to the low abundance and low sensitivity of C nuclei. The longer acquisition time for C NMR results in a loss of precious spectrometer time in a shared multi-user environment. A regular 5 mm o.d. NMR tube is the most commonly used tube for NMR in organic chemistry labs and is also the cheapest option. We show that for analytes soluble in the CDCl solvent using a regular 5 mm o.d. NMR tube, the speed of C observation can be enhanced by a factor of two by resorting to a sample preparation method that employs a biphasic system made of HO or DO at the top of another layer of CDCl. By using the biphasic system of two immiscible solvents, the analyte can be concentrated in the CDCl layer (within the more sensitive volume of the NMR coil), resulting in the improvement of the signal to noise ratio (SNR) by a factor of up to 1.8 for C and 2D H-C HSQC spectra, which results in more than two-fold reduction in the experimental time. H NMR and other 2D NMR also get a sensitivity boost. The amount of CDCl required for sample preparation can also be reduced by 40% using this biphasic system (CDCl/HO). Sample preparation in such an immiscible biphasic system is effortless and straightforward. The performance of such biphasic samples is closer to that of Shigemi tubes and better than that of 3 mm o.d. tubes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/d1an00470kDOI Listing
October 2021

Pesticides DEET, fipronil and maneb induce stress granule assembly and translation arrest in neuronal cells.

Biochem Biophys Rep 2021 Dec 25;28:101110. Epub 2021 Aug 25.

Department of Biological Sciences and Bioengineering, India.

Pesticides entering our body, either directly or indirectly, are known to increase the risk of developing neurodegenerative disorders. The pesticide-induced animal models of Parkinson's disease and Alzheimer's disease recapitulates many of the pathologies seen in human patients and have become popular models for studying disease biology. However, the specific effect of pesticides at the cellular and molecular levels is yet to be fully established. Here we investigated the cellular effect of three commonly used pesticides: DEET, fipronil and maneb. Specifically, we looked at the effect of these pesticides in the formation of stress granules and the concomitant translational arrest in a neuronal cell line. Stress granules represent an ensemble of non-translating mRNAs and appear in cells under physiological stress. Growing evidence indicates that chronic stress may covert the transient stress granules into amyloids and may thus induce neurodegeneration. We demonstrate here that all three pesticides tested induce stress granules and translation arrest through the inactivation of the eukaryotic initiation factor, eIF2α. We also show that oxidative stress could be one of the major intermediary factors in the pesticide-induced stress granule formation and that it is a reversible process. Our results suggest that prolonged pesticide exposure may result in long-lived stress granules, thus compromising the neuronal stress response pathway and leading to neurodegeneration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbrep.2021.101110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8405967PMC
December 2021

Discovery of Arginine Ethyl Ester as Polyglutamine Aggregation Inhibitor: Conformational Transitioning of Huntingtin N-Terminus Augments Aggregation Suppression.

ACS Chem Neurosci 2019 09 10;10(9):3969-3985. Epub 2019 Sep 10.

Biological Sciences and Bioengineering , Indian Institute of Technology Kanpur , Kanpur , Uttar Pradesh 208016 , India.

Huntington's disease (HD) is a genetic disorder caused by a CAG expansion mutation in the gene leading to polyglutamine (polyQ) expansion in the N-terminal part of huntingtin (Httex1). Expanded polyQ, through a complex aggregation pathway, forms aggregates in neurons and presents a potential therapeutic target. Here we show Httex1 aggregation suppression by arginine and arginine ethyl ester (AEE) , as well as in yeast and mammalian cell models of HD, bearing expanded polyQ. These molecules also rescue locomotion dysfunction in HD model. Both molecules alter the hydrogen bonding network of polyQ to enhance its aqueous solubility and delay aggregation. AEE shows direct binding with the NT part of Httex1 to induce structural changes to impart an enhanced inhibitory effect. This study provides a platform for the development of better arginine based therapeutic molecules against polyQ-rich Httex1 aggregation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acschemneuro.9b00167DOI Listing
September 2019

Identification of metabolites in coriander seeds (Coriandrum Sativum L.) aided by ultrahigh resolution total correlation NMR spectroscopy.

Magn Reson Chem 2019 06 18;57(6):304-316. Epub 2019 Mar 18.

Centre of Biomedical Research, SGPGIMS Campus, Lucknow, UP, India.

NMR is a fast method for obtaining a holistic snapshot of the metabolome and also offers quantitative information without separating the compounds present in a complex mixture. Identification of the metabolites present in a plant extract sample is a crucial step for all plant metabolomics studies. In the present work, we used various two dimensional (2D) NMR methods such as J-resolved NMR, total correlation spectroscopy (TOCSY), and heteronuclear single quantum coherence sensitivity enhanced NMR spectroscopy for the identification of 36 common metabolites present in Coriandrum sativum L. seed extract. The identified metabolites belong to the following classes: organic acids, amino acids, and carbohydrates. H NMR spectra of such complex mixtures in general display tremendous signal overlap due to the presence of a large number of metabolites with closely resonating multiplet signals. This signal overlapping leads to ambiguity in an assignment, and hence, identification of metabolites becomes tedious or impossible in many cases. Therefore, the utility of pure-shift proton spectrum along the indirect (F ) dimension of the F -PSYCHE-TOCSY spectrum is demonstrated for overcoming ambiguity in assignment of metabolites in crowded spectral regions from Coriandrum sativum L. seed extract sample. Because pure-shift NMR methods yield ultrahigh resolution spectrum (i.e., a singlet peak per chemical site) along one or more dimensions, such spectra provide better identification of metabolites compared with regular 2D TOCSY where signal overlap and peak distortions lead to ambiguity in the assignment. Nine metabolites were unambiguously assigned by pure-shift F -PSYCHE-TOCSY spectrum, which was unresolved in regular TOCSY spectrum.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mrc.4850DOI Listing
June 2019

Correction to: Interdependence of laforin and malin proteins for their stability and functions could underlie the molecular basis of locus heterogeneity in Lafora disease.

J Biosci 2018 Sep;43(4):817

Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur 208 016, India.

Correction to: J. Biosci. 40(5), December 2015, 863-871 https://doi.org/10.1007/s12038-015-9570-0 The image of anti-Myc blot of figure 2C (third panel; Malin-Myc [C26S]) was inadvertently used once again for the c-tubulin loading control of figure 2B. The revised figure 2B with the correct image of the c-tubulin loading control is given below. The interpretation and conclusion provided in the article do not change because of the correction.
View Article and Find Full Text PDF

Download full-text PDF

Source
September 2018

Lafora disease: from genotype to phenotype.

J Genet 2018 Jul;97(3):611-624

Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur, Kanpur 208 016, India.

The progressive myoclonic epilepsy of Lafora or Lafora disease (LD) is a neurodegenerative disorder characterized by recurrent seizures and cognitive deficits. With typical onset in the late childhood or early adolescence, the patients show progressive worsening of the disease symptoms, leading to death in about 10 years. It is an autosomal recessive disorder caused by the loss-of-function mutations in the gene, coding for a protein phosphatase (laforin) or the gene coding for an E3 ubiquitin ligase (malin). LD is characterized by the presence of abnormally branched water insoluble glycogen inclusions known as Lafora bodies in the neurons and other tissues, suggesting a role for laforin and malin in glycogen metabolic pathways. Mouse models of LD, developed by targeted disruption of the or gene, recapitulated most of the symptoms and pathological features as seen in humans, and have offered insight into the pathomechanisms. Besides the formation of Lafora bodies in the neurons in the presymptomatic stage, the animal models have also demonstrated perturbations in the proteolytic pathways, such as ubiquitin proteasome system and autophagy, and inflammatory response. This review attempts to provide a comprehensive coverage on the genetic defects leading to the LD in humans, on the functional properties of the laforin and malin proteins, and on how defects in any one of these two proteins result in a clinically similar phenotype. We also discuss the disease pathologies as revealed by the studies on the animal models and, finally, on the progress with therapeutic attempts albeit in the animal models.
View Article and Find Full Text PDF

Download full-text PDF

Source
July 2018

Analyses of Complex Mixtures by F Homo-Decoupled Diagonal Suppressed Total Correlation Spectroscopy.

Chemphyschem 2017 Nov 9;18(21):3076-3082. Epub 2017 Oct 9.

Centre of Biomedical Research (Formerly Centre of Biomedical Magnetic Resonance), SGPGIMS Campus, Raebareli Road, Lucknow, 226014, U. P., India.

A diagonal suppressed F decoupled total correlation spectroscopy(TOCSY) experiment is developed for analyses of complex mixtures. In 2D homonuclear correlation, assignment of the cross peaks is crucial for structure elucidation. However, when cross peaks are close to the diagonal peaks in overcrowded spectral regions, their assignment becomes tedious. In complex mixtures, the presence of multiple spectra along with broad and complex proton multiplets owing to homonuclear scalar couplings degrade the resolution to the extent that assignment of various cross peaks becomes tedious or impossible. Herein, a diagonal suppressed total correlation technique with F decoupling is presented to improve the resolution of the cross peaks. The resolution of the cross peaks is improved by both diagonal suppression as well as the collapse of the multiplets to singlets. Application of the method to a few mixtures of organic compounds reveals better identification of the cross peaks relative to other TOCSY variants.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cphc.201700662DOI Listing
November 2017

Autism genes: the continuum that connects us all.

J Genet 2016 09;95(3):481-3

Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur, 208 016, India.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12041-016-0688-0DOI Listing
September 2016

Human satellite-III non-coding RNAs modulate heat-shock-induced transcriptional repression.

J Cell Sci 2016 10 15;129(19):3541-3552. Epub 2016 Aug 15.

Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur 208016, India

The heat shock response is a conserved defense mechanism that protects cells from physiological stress, including thermal stress. Besides the activation of heat-shock-protein genes, the heat shock response is also known to bring about global suppression of transcription; however, the mechanism by which this occurs is poorly understood. One of the intriguing aspects of the heat shock response in human cells is the transcription of satellite-III (Sat3) long non-coding RNAs and their association with nuclear stress bodies (nSBs) of unknown function. Besides association with the Sat3 transcript, the nSBs are also known to recruit the transcription factors HSF1 and CREBBP, and several RNA-binding proteins, including the splicing factor SRSF1. We demonstrate here that the recruitment of CREBBP and SRSF1 to nSBs is Sat3-dependent, and that loss of Sat3 transcripts relieves the heat-shock-induced transcriptional repression of a few target genes. Conversely, forced expression of Sat3 transcripts results in the formation of nSBs and transcriptional repression even without a heat shock. Our results thus provide a novel insight into the regulatory role for the Sat3 transcripts in heat-shock-dependent transcriptional repression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1242/jcs.189803DOI Listing
October 2016

Interdependence of laforin and malin proteins for their stability and functions could underlie the molecular basis of locus heterogeneity in Lafora disease.

J Biosci 2015 Dec;40(5):863-71

Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur 208 016, India.

Lafora disease (LD), an autosomal recessive and fatal form of neurodegenerative disorder, is characterized by the presence of polyglucosan inclusions in the affected tissues including the brain. LD can be caused by defects either in the EPM2A gene coding for the laforin protein phosphatase or the NHLRC1 gene coding for the malin ubiquitin ligase. Since the clinical symptoms of LD patients representing the two genetic groups are very similar and since malin is known to interact with laforin, we were curious to examine the possibility that the two proteins regulate each other's function. Using cell biological assays we demonstrate here that (i) malin promotes its own degradation via autoubiquitination, (ii) laforin prevents the auto-degradation of malin by presenting itself as a substrate and (iii) malin preferentially degrades the phosphatase-inactive laforin monomer. Our results that laforin and malin regulate each other's stability and activity offers a novel and attractive model to explain the molecular basis of locus heterogeneity observed in LD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12038-015-9570-0DOI Listing
December 2015

Association of the GRM4 gene variants with juvenile myoclonic epilepsy in an Indian population.

J Genet 2014 Apr;93(1):193-7

Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur 208 016, India.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12041-014-0334-7DOI Listing
April 2014

Decreased O-linked GlcNAcylation protects from cytotoxicity mediated by huntingtin exon1 protein fragment.

J Biol Chem 2014 May 19;289(19):13543-53. Epub 2014 Mar 19.

From the Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur 208016 and.

O-GlcNAcylation is an important post-translational modification of proteins and is known to regulate a number of pathways involved in cellular homeostasis. This involves dynamic and reversible modification of serine/threonine residues of different cellular proteins catalyzed by O-linked N-acetylglucosaminyltransferase and O-linked N-acetylglucosaminidase in an antagonistic manner. We report here that decreasing O-GlcNAcylation enhances the viability of neuronal cells expressing polyglutamine-expanded huntingtin exon 1 protein fragment (mHtt). We further show that O-GlcNAcylation regulates the basal autophagic process and that suppression of O-GlcNAcylation significantly increases autophagic flux by enhancing the fusion of autophagosome with lysosome. This regulation considerably reduces toxic mHtt aggregates in eye imaginal discs and partially restores rhabdomere morphology and vision in a fly model for Huntington disease. This study is significant in unraveling O-GlcNAcylation-dependent regulation of an autophagic process in mediating mHtt toxicity. Therefore, targeting the autophagic process through the suppression of O-GlcNAcylation may prove to be an important therapeutic approach in Huntington disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1074/jbc.M114.553321DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4036360PMC
May 2014

The SCN1A gene variants and epileptic encephalopathies.

J Hum Genet 2013 Sep 25;58(9):573-80. Epub 2013 Jul 25.

1] Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur, India [2] Department of Biochemistry, G.R.Medical College, Gwalior, India.

The voltage-gated sodium channels are fundamental units that evoke the action potential in excitable cells such as neurons. These channels are integral membrane proteins typically consisting of one α-subunit, which forms the larger central pore of the channel, and two smaller auxiliary β-subunits, which modulate the channel functions. Genetic alterations in the SCN1A gene coding for the α-subunit of the neuronal voltage-gated sodium ion channel, type 1 (NaV 1.1), is associated with a spectrum of seizure-related disorders in human, ranging from a relatively milder form of febrile seizures to a more severe epileptic condition known as the Dravet syndrome. Among the epilepsy genes, the SCN1A gene perhaps known to have the largest number of disease-associated alleles. Here we present a meta-analysis on the SCN1A gene variants and provide comprehensive information on epilepsy-associated gene variants, their frequency, the predicted effect on the protein, the ethnicity of the affected along with the inheritance pattern and the associated epileptic phenotype. We also summarize our current understanding on the pathophysiology of the SCN1A gene defects, disease mechanism, genetic modifiers and their clinical and diagnostic relevance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/jhg.2013.77DOI Listing
September 2013

Novel chemosensor for the visual detection of copper(II) in aqueous solution at the ppm level.

Inorg Chem 2012 Aug 6;51(16):8664-6. Epub 2012 Aug 6.

Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur, India.

A new water-soluble, multisite-coordinating ligand LH(7) was prepared by the condensation of tris(hydroxymethyl)aminomethane with 2,6-diformyl-p-cresol. LH(7) is a selective chemosensor for Cu(2+), under physiological conditions, with visual detection limits of 20 ppm (ambient light conditions) and 4 ppm (UV light conditions). LH(7) can also be used in biological cell lines for the detection of Cu(2+).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/ic301399aDOI Listing
August 2012

Identification and characterization of novel splice variants of the human EPM2A gene mutated in Lafora progressive myoclonus epilepsy.

Genomics 2012 Jan 19;99(1):36-43. Epub 2011 Oct 19.

Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur, 208016, India.

The EPM2A gene, defective in the fatal neurodegenerative disorder Lafora disease (LD), is known to encode two distinct proteins by differential splicing; a phosphatase active cytoplasmic isoform and a phosphatase inactive nuclear isoform. We report here the identification of three novel EPM2A splice variants with potential to code for five distinct proteins in alternate reading frames. These novel isoforms, when ectopically expressed in cell lines, show distinct subcellular localization, interact with and serve as substrates of malin ubiquitin ligase-the second protein defective in LD. Two phosphatase active isoforms interact to form a heterodimeric complex that is inactive as a phosphatase in vitro, suggesting an antagonistic function for laforin isoforms if expressed endogenously in significant amounts in human tissues. Thus alternative splicing could possibly be one of the mechanisms by which EPM2A may regulate the cellular functions of the proteins it codes for.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ygeno.2011.10.001DOI Listing
January 2012

Proline repeats, in cis- and trans-positions, confer protection against the toxicity of misfolded proteins in a mammalian cellular model.

Neurosci Res 2011 Aug 17;70(4):435-41. Epub 2011 May 17.

Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kalyanpur, Kanpur, UP 208016, India.

A broad range of neurodegenerative disorders result from the cytotoxicity conferred by aberrantly folded mutant proteins. Intriguingly, the cytotoxicity and aggregation property of a few mutant proteins are known to be modulated by the flanking sequences. One of such modulators is the proline repeat tract. Using a mammalian cellular model, we show here that proline repeat tract, both in cis- and in trans-positions, ameliorate the cytotoxicity of wide range of misfolded proteins coded by synthetic constructs. We further show that the proline repeat tract could possibly confer protection against the cytotoxicity of misfolded proteins by altering their conformation at the time of their synthesis. Thus, our study elucidates the mechanism by which the proline repeat tract might ameliorate the toxicity of misfolded proteins, and opens up new therapeutic modalities for disorders caused by cytotoxic misfolded proteins.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neures.2011.05.001DOI Listing
August 2011

Satellite III non-coding RNAs show distinct and stress-specific patterns of induction.

Biochem Biophys Res Commun 2009 Apr 1;382(1):102-7. Epub 2009 Mar 1.

Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur 208 016, India.

The heat shock response in human cells is associated with the transcription of satellite III repeats (SatIII) located in the 9q12 locus. Upon induction, the SatIII transcripts remain associated with the locus and recruit several transcription and splicing factors to form the nuclear stress bodies (nSBs). The nSBs are thought to modulate epigenetic changes during the heat shock response. We demonstrate here that the nSBs are induced by a variety of stressors and show stress-specific patterns of induction. While the transcription factor HSF1 is required for the induction of SatIII locus by the stressors tested, its specific role in the transcriptional process appears to be stress dependent. Our results suggest the existence of multiple transcriptional loci for the SatIII transcripts and that their activation might depend upon the type of stressors. Thus, induction of SatIII transcripts appears to be a generic response to a variety of stress conditions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbrc.2009.02.137DOI Listing
April 2009

Spatial positions of homopolymeric repeats in the human proteome and their effect on cellular toxicity.

Biochem Biophys Res Commun 2009 Mar 23;380(2):382-6. Epub 2009 Jan 23.

Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kalyanpur, Kanpur 208016, India.

Proteins with homopolymeric repeat tracts are very common in the human proteome. Intriguingly, some but not all repeat tracts show length variation in the population and, in a few, the expansion of repeat tract beyond the normal length is associated with neurodegenerative and developmental disorders. In this study we have addressed questions such as why some amino acid residues are favored in longer repeat tracts and why repeat tracts show terminal bias. Using cell biological assays for repeat tracts fused to green fluorescent protein we show here that homopolymeric repeats that are beyond their naturally occurring length in the proteome are cytotoxic in nature. This toxicity is further modulated by the length of the peptide that bears the repeat and the spatial location of the repeat within the peptide. Thus, the cellular toxicity appears to be one of the selective processes that regulate the evolution of homopolymeric repeats in the proteome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbrc.2009.01.101DOI Listing
March 2009

The malin-laforin complex suppresses the cellular toxicity of misfolded proteins by promoting their degradation through the ubiquitin-proteasome system.

Hum Mol Genet 2009 Feb 25;18(4):688-700. Epub 2008 Nov 25.

Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur, India.

Lafora disease (LD), a progressive form of inherited epilepsy, is associated with widespread neurodegeneration and the formation of polyglucosan bodies in the neurons. Laforin, a protein phosphatase, and malin, an E3 ubiquitin ligase, are two of the proteins that are defective in LD. We have shown recently that laforin and malin (referred together as LD proteins) are recruited to aggresome upon proteasomal blockade, possibly to clear misfolded proteins through the ubiquitin-proteasome system (UPS). Here we test this possibility using a variety of cytotoxic misfolded proteins, including the expanded polyglutamine protein, as potential substrates. Laforin and malin, together with Hsp70 as a functional complex, suppress the cellular toxicity of misfolded proteins, and all the three members of this complex are required for this function. Laforin and malin interact with misfolded proteins and promote their degradation through the UPS. LD proteins are recruited to the polyglutamine aggregates and reduce the frequency of aggregate-positive cells. Taken together, our results suggest that the malin-laforin complex is a novel player in the neuronal response to misfolded proteins and could be potential therapeutic targets for neurodegenerative disorders associated with cytotoxic proteins.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/hmg/ddn398DOI Listing
February 2009

Association between inflammatory gene polymorphisms and coronary artery disease in an Indian population.

J Thromb Thrombolysis 2009 Jan 23;27(1):88-94. Epub 2007 Dec 23.

Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur, 208016, India.

Background: Inflammation is one of the major components of atherosclerosis which is the underlying disorder that leads to various diseases including coronary artery disease (CAD). Genes that are involved in the inflammatory processes are therefore good candidates for the risk of CAD. Variations in the genes involved in various molecular pathways of inflammation have been implicated to exaggerated atherosclerosis and the risk of cardiovascular diseases. In this study, we performed a genetic association study on the single nucleotide polymorphisms (SNPs) present in the genes CD14 (-159 C/T), TNFalpha (-308 G/A), IL-1alpha (-889 C/T), IL-6 (-174 G/C), PSMA6 (-8 C/G), and PDE4D (SNP83 T/C, respectively) in order to discern their possible role in the susceptibility to CAD in a North Indian population.

Methods: Angiographically proven CAD patients (n = 210) and age, sex and ethnically matched normal healthy controls (n = 232) were recruited for this case-control study. Genotypes were determined by PCR-RFLP method. Chi-square and logistic regression analyses were performed to compare the genotype and allele frequencies between the patient and the control groups.

Results: None of the SNPs showed significant association with CAD in the study population before and after adjustment for the confounding risk factors like age, sex, hypertension, smoking habit, and diabetes.

Conclusion: This study was unable to demonstrate any association between the six gene variants tested and CAD in the North Indian population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11239-007-0184-8DOI Listing
January 2009
-->