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Involvement of autophagy in hypoxic-excitotoxic neuronal death

Vanessa Ginet, Amélie Spiehlmann, Coralie Rummel, Nikita Rudinskiy, Yulia Grishchuk, Ruth Luthi-Carter, Peter GH Clarke, Anita C Truttmann, Julien Puyal
2014 Autophagy  
doi:10.4161/auto.28264 pmid:24674959 pmcid:PMC5119065 fatcat:tdv3vwcd25dndlie7jwddox7tq

Folylpoly-γ-glutamate Carboxypeptidase from Pig Jejunum

Charles H. Halsted, Erh-hsin Ling, Ruth Luthi-Carter, Jesus A. Villanueva, John M. Gardner, Joseph T. Coyle
1998 Journal of Biological Chemistry  
Jejunal folylpoly-␥-glutamate carboxypeptidase hydrolyzes dietary folates prior to their intestinal absorption. The complete folylpoly-␥-glutamate carboxypeptidase cDNA was isolated from a pig jejunal cDNA library using an amplified homologous probe incorporating primer sequences from prostate-specific membrane antigen, a protein capable of folate hydrolysis. The cDNA encodes a 751-amino acid polypeptide homologous to prostate-specific membrane antigen and rat brain Nacetylated ␣-linked acidic
more » ... ipeptidase. PC3 transfectant membranes exhibited activities of folylpoly-␥-carboxypeptidase and N-acetylated ␣-linked acidic dipeptidase, while immunoblots using monoclonal antibody to native folylpoly-␥-glutamate carboxypeptidase identified a glycoprotein at 120 kDa and a polypeptide at 84 kDa. The kinetics of native folylpoly-␥-carboxypeptidase were expressed in membranes of PC3 cells transfected with either pig folylpoly-␥-carboxypeptidase or human prostate-specific membrane antigen. Folylpoly-␥-carboxypeptidase transcripts were identified at 2.8 kilobase pairs in human and pig jejunum, human and rat brain, and human prostate cancer LNCaP cells. Thus, pig folylpoly-␥-carboxypeptidase, rat N-acetylated ␣-linked acidic dipeptidase, and human prostate-specific membrane antigen appear to represent varied expressions of the same gene in different species and tissues. The discovery of the jejunal folylpoly-␥carboxypeptidase gene provides a framework for future studies on relationships among these proteins and on the molecular regulation of intestinal folate absorption. We suggest that subscribers photocopy these corrections and insert the photocopies at the appropriate places where the article to be corrected originally appeared. Authors are urged to introduce these corrections into any reprints they distribute. Secondary (abstract) services are urged to carry notice of these corrections as prominently as they carried the original abstracts. 30746
doi:10.1074/jbc.273.32.20417 pmid:9685395 fatcat:25pcjoslbzcatjjskfixq47g7u

Cross-species and cross-platform gene expression studies with the Bioconductor-compliant R package 'annotationTools'

Alexandre Kuhn, Ruth Luthi-Carter, Mauro Delorenzi
2008 BMC Bioinformatics  
The variety of DNA microarray formats and datasets presently available offers an unprecedented opportunity to perform insightful comparisons of heterogeneous data. Cross-species studies, in particular, have the power of identifying conserved, functionally important molecular processes. Validation of discoveries can now often be performed in readily available public data which frequently requires cross-platform studies. Cross-platform and cross-species analyses require matching probes on
more » ... t microarray formats. This can be achieved using the information in microarray annotations and additional molecular biology databases, such as orthology databases. Although annotations and other biological information are stored using modern database models (e.g. relational), they are very often distributed and shared as tables in text files, i.e. flat file databases. This common flat database format thus provides a simple and robust solution to flexibly integrate various sources of information and a basis for the combined analysis of heterogeneous gene expression profiles. Results: We provide annotationTools, a Bioconductor-compliant R package to annotate microarray experiments and integrate heterogeneous gene expression profiles using annotation and other molecular biology information available as flat file databases. First, annotationTools contains a specialized set of functions for mining this widely used database format in a systematic manner. It thus offers a straightforward solution for annotating microarray experiments. Second, building on these basic functions and relying on the combination of information from several databases, it provides tools to easily perform cross-species analyses of gene expression data. Here, we present two example applications of annotationTools that are of direct relevance for the analysis of heterogeneous gene expression profiles, namely a cross-platform mapping of probes and a cross-species mapping of orthologous probes using different orthology databases. We also show how to perform an explorative comparison of disease-related transcriptional changes in human patients and in a genetic mouse model. Conclusion: The R package annotationTools provides a simple solution to handle microarray annotation and orthology tables, as well as other flat molecular biology databases. Thereby, it allows easy integration and analysis of heterogeneous microarray experiments across different technological platforms or species.
doi:10.1186/1471-2105-9-26 pmid:18201381 pmcid:PMC2267709 fatcat:btgfumnp3fgc3l4mplip34goem

Tubulin and Tubulin Posttranslational Modifications in Alzheimer's Disease and Vascular Dementia

Estibaliz Santiago-Mujika, Ruth Luthi-Carter, Flaviano Giorgini, Raj N. Kalaria, Elizabeta B. Mukaetova-Ladinska
2021 Frontiers in Aging Neuroscience  
Alzheimer's disease (AD) and vascular dementia (VaD) are the two most common forms of dementia in older people. Although these two dementia types differ in their etiology, they share many pathophysiological and morphological features, including neuronal loss, which is associated with the microtubule (MT) destabilization. Stabilization of MTs is achieved in different ways: through interactions with MT binding proteins (MTBP) or by posttranslational modifications (PTMs) of tubulin.
more » ... on and tyrosination are two foremost PTMs that regulate the interaction between MTs and MTBPs, and play, therefore, a role in neurodegeneration. In this review, we summarize key information on tubulin PTMs in relation to AD and VaD and address the importance of studying further the tubulin code to reveal sites of potential intervention in development of novel and effective dementia therapy.
doi:10.3389/fnagi.2021.730107 pmid:34776926 pmcid:PMC8586541 fatcat:6jzfjstc2reglonknbuxuij5ha

Expression analysis of novel striatal-enriched genes in Huntington disease

Gelareh Mazarei, Scott J. Neal, Kristina Becanovic, Ruth Luthi-Carter, Elizabeth M. Simpson, Blair R. Leavitt
2009 Human Molecular Genetics  
Selective degeneration of striatal neurons is a pathologic hallmark of Huntington disease (HD). The exact mechanism(s) behind this specific neurodegeneration is still unknown. Expression studies of diseased human post-mortem brain, as well as different mouse models exhibiting striatal degeneration, have demonstrated changes in the expression of many important genes with a large proportion of changes being observed in the striatal-enriched genes. These investigations have raised questions about
more » ... ow enrichment of particular transcripts in the striatum can lead to its selective vulnerability to neurodegeneration. Monitoring the expression changes of striatal-enriched genes during the course of the disease may be informative about their potential involvement in selective degeneration. In this study, we analyzed a Serial Analysis of Gene Expression (SAGE) database (www.mouseatlas.org) and compared the mouse striatum to 18 other brain regions to generate a novel list of striatal-enriched transcripts. These novel striatal-enriched transcripts were subsequently evaluated for expression changes in the YAC128 mouse model of HD, and differentially expressed transcripts were further examined in human post-mortem caudate samples. We identified transcripts with altered expression in YAC128 mice, which also showed consistent expression changes in human post-mortem tissue. The identification of novel striatal-enriched genes with altered expression in HD offers new avenues of study, leading towards a better understanding of specific pathways involved in the selective degeneration of striatal neurons in HD.
doi:10.1093/hmg/ddp527 pmid:19934114 pmcid:PMC2807369 fatcat:37q56u3kk5fkrh36gwbbmjscoa

Longitudinal Expression Changes Are Weak Correlates Of Disease Progression In Huntington's Disease

Christopher T Mitchell, Irina Krier, Jamshid Arjomand, Beth Borowsky, Sarah J Tabrizi, Blair R Leavitt, Ruth Luthi-Carter, TRACK-HD Investigators
2020 Brain Communications  
function and behavioural disturbances (Luthi-Carter et al., 2002a; Kuhn et al., 2007; Giles et al., 2012) .  ...  Huntington's disease pathogenesis is complex, involving multiple cellular mechanisms including protein aggregation, mitochondrial dysfunction and transcriptional dysregulation (Luthi-Carter, 2007) .  ... 
doi:10.1093/braincomms/fcaa172 pmid:33305259 pmcid:PMC7713990 fatcat:mg34hy7hfnhm7fmbmu5pq3cfce

Comparison of meta-analysis to combined analysis of a replicated microarray study [chapter]

Ruth Luthi-Carter, Darlene Goldstein, Thierry Sengstag, Mauro Delorenzi
2009 Meta-analysis and Combining Information in Genetics and Genomics  
doi:10.1201/9781420010626.ch9 fatcat:vpl2plufl5gkzjzxo7ikirbyja

Short-Term Striatal Gene Expression Responses to Brain-Derived Neurotrophic Factor Are Dependent on MEK and ERK Activation

Ozgun Gokce, Heike Runne, Alexandre Kuhn, Ruth Luthi-Carter, Colin Combs
2009 PLoS ONE  
Brain-derived neurotrophic factor (BDNF) is believed to be an important regulator of striatal neuron survival, differentiation, and plasticity. Moreover, reduction of BDNF delivery to the striatum has been implicated in the pathophysiology of Huntington's disease. Nevertheless, many essential aspects of BDNF responses in striatal neurons remain to be elucidated. Methodology/Principal Findings: In this study, we assessed the relative contributions of multipartite intracellular signaling pathways
more » ... to the short-term induction of striatal gene expression by BDNF. To identify genes regulated by BDNF in these GABAergic cells, we first used DNA microarrays to quantify their transcriptomic responses following 3 h of BDNF exposure. The signal transduction pathways underlying gene induction were subsequently dissected using pharmacological agents and quantitative real-time PCR. Gene expression responses to BDNF were abolished by inhibitors of TrkB (K252a) and calcium (chelator BAPTA-AM and transient receptor potential cation channel [TRPC] antagonist SKF-96365). Interestingly, inhibitors of mitogen-activated protein kinase kinases 1 and 2 (MEK1/2) and extracellular signal-regulated kinase ERK also blocked the BDNF-mediated induction of all tested BDNF-responsive genes. In contrast, inhibitors of nitric oxide synthase (NOS), phosphotidylinositol-3-kinase (PI3K), and CAMK exhibited less prevalent, gene-specific effects on BDNF-induced RNA expression. At the nuclear level, the activation of both Elk-1 and CREB showed MEK dependence. Importantly, MEKdependent activation of transcription was shown to be required for BDNF-induced striatal neurite outgrowth, providing evidence for its contribution to striatal neuron plasticity. Conclusions: These results show that the MEK/ERK pathway is a major mediator of neuronal plasticity and other important BDNF-dependent striatal functions that are fulfilled through the positive regulation of gene expression.
doi:10.1371/journal.pone.0005292 pmid:19390590 pmcid:PMC2669182 fatcat:sapx5aepk5cvva6c7d76yj6xm4

Connectivity mapping uncovers small molecules that modulate neurodegeneration in Huntington's disease models

Joshua L. Smalley, Carlo Breda, Robert P. Mason, Gurdeep Kooner, Ruth Luthi-Carter, Timothy W. Gant, Flaviano Giorgini
2015 Journal of Molecular Medicine  
Huntington's disease (HD) is a genetic disease caused by a CAG trinucleotide repeat expansion encoding a polyglutamine tract in the huntingtin (HTT) protein, ultimately leading to neuronal loss and consequent cognitive decline and death. As no treatments for HD currently exist, several chemical screens have been performed using cell-based models of mutant HTT toxicity. These screens measured single disease-related endpoints, such as cell death, but had low 'hit rates' and limited dimensionality for therapeutic detection.
doi:10.1007/s00109-015-1344-5 pmid:26428929 pmcid:PMC4762922 fatcat:tglqhtczsfeqbofgp63jbeb2nm

Decreased Striatal RGS2 Expression Is Neuroprotective in Huntington's Disease (HD) and Exemplifies a Compensatory Aspect of HD-Induced Gene Regulation

Tamara Seredenina, Ozgun Gokce, Ruth Luthi-Carter, Xiao-Jiang Li
2011 PLoS ONE  
The molecular phenotype of Huntington's disease (HD) is known to comprise highly reproducible changes in gene expression involving striatal signaling genes. Here we test whether individual changes in striatal gene expression are capable of mitigating HD-related neurotoxicity. Methodology/Principal Findings: We used protein-encoding and shRNA-expressing lentiviral vectors to evaluate the effects of RGS2, RASD2, STEP and NNAT downregulation in HD. Of these four genes, only RGS2 and RASD2 modified
more » ... mutant htt fragment toxicity in cultured rat primary striatal neurons. In both cases, disease modulation was in the opposite of the predicted direction: whereas decreased expression of RGS2 and RASD2 was associated with the HD condition, restoring expression enhanced degeneration of striatal cells. Conversely, silencing of RGS2 or RASD2 enhanced disease-related changes in gene expression and resulted in significant neuroprotection. These results indicate that RGS2 and RASD2 downregulation comprises a compensatory response that allows neurons to better tolerate huntingtin toxicity. Assessment of the possible mechanism of RGS2-mediated neuroprotection showed that RGS2 downregulation enhanced ERK activation. These results establish a novel link between the inhibition of RGS2 and neuroprotective modulation of ERK activity. Conclusions: Our findings both identify RGS2 downregulation as a novel compensatory response in HD neurons and suggest that RGS2 inhibition might be considered as an innovative target for neuroprotective drug development.
doi:10.1371/journal.pone.0022231 pmid:21779398 pmcid:PMC3136499 fatcat:dhlsupbi3jhe5a2ixpjbzcttba

Computational deconvolution of genome wide expression data from Parkinson's and Huntington's disease brain tissues using population-specific expression analysis

Alberto Capurro, Liviu-Gabriel Bodea, Patrick Schaefer, Ruth Luthi-Carter, Victoria M. Perreau
2015 Frontiers in Neuroscience  
This work was also funded by the University of Leicester (Ruth Luthi-Carter, Alberto Capurro).  ...  Copyright © 2015 Capurro, Bodea, Schaefer, Luthi-Carter and Perreau. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY).  ...  Citation: Capurro A, Bodea L-G, Schaefer P, Luthi-Carter R and Perreau VM (2015) Computational deconvolution of genome wide expression data from Parkinson's and Huntington's disease brain tissues using  ... 
doi:10.3389/fnins.2014.00441 pmid:25620908 pmcid:PMC4288238 fatcat:ho2z6gqt5fgkhjsvhfezfazpe4

Evolution Of Protein Misfolding And Cell Apoptosis In Huntington's Disease Studied By Synchrotron Infra-Red Microspectroscopy

Markus Bonda, Heike Runne, Bertrand Vileno, Valérie Perrin, Ariane Kretlow, Lisa M. Miller, László Forró, Ruth Lüthi-Carter, Sylvia Jeney
2009 Biophysical Journal  
Miller 4 , László Forró 1 , Ruth Lüthi-Carter 1 , Sylvia Jeney 1 . 1 Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland, 2 Florida State University, Tallahassee, FL, USA, 3 AC Immune  ... 
doi:10.1016/j.bpj.2008.12.356 fatcat:byliz3p4qnd5jcyieuewex5tuq

Calpain Hydrolysis of α- and β2-Adaptins Decreases Clathrin-dependent Endocytosis and May Promote Neurodegeneration

Nikita Rudinskiy, Yulia Grishchuk, Anne Vaslin, Julien Puyal, André Delacourte, Harald Hirling, Peter G. H. Clarke, Ruth Luthi-Carter
2009 Journal of Biological Chemistry  
Clathrin-dependent endocytosis is mediated by a tightly regulated network of molecular interactions that provides essential protein-protein and protein-lipid binding activities. Here we report the hydrolysis of the ␣and ␤2-subunits of the tetrameric adaptor protein complex 2 by calpain. Calcium-dependent ␣and ␤2-adaptin hydrolysis was observed in several rat tissues, including brain and primary neuronal cultures. Neuronal ␣and ␤2-adaptin cleavage was inducible by glutamate stimulation and was
more » ... companied by the decreased endocytosis of transferrin. Heterologous expression of truncated forms of the ␤2-adaptin subunit significantly decreased the membrane recruitment of clathrin and inhibited clathrin-mediated receptor endocytosis. Moreover, the presence of truncated ␤2-adaptin sensitized neurons to glutamate receptor-mediated excitotoxicity. Proteolysis of ␣and ␤2-adaptins, as well as the accessory clathrin adaptors epsin 1, adaptor protein 180, and the clathrin assembly lymphoid myeloid leukemia protein, was detected in brain tissues after experimentally induced ischemia and in cases of human Alzheimer disease. The present study further clarifies the central role of calpain in regulating clathrin-dependent endocytosis and provides evidence for a novel mechanism through which calpain activation may promote neurodegeneration: the sensitization of cells to glutamate-mediated excitotoxicity via the decreased internalization of surface receptors.
doi:10.1074/jbc.m804740200 pmid:19240038 pmcid:PMC2673311 fatcat:rzzirbyqmna6ti3oywsaly73am

Cell loss in the motor and cingulate cortex correlates with symptomatology in Huntington's disease

Doris C. V. Thu, Dorothy E. Oorschot, Lynette J. Tippett, Alissa L. Nana, Virginia M. Hogg, Beth J. Synek, Ruth Luthi-Carter, Henry J. Waldvogel, Richard L. M. Faull
2010 Brain  
Abbreviations: NeuN = neuronal N; N v = numerical density; V ref = reference volume Cell loss in Huntington's disease cortex Brain
doi:10.1093/brain/awq047 pmid:20375136 fatcat:qt4llivypbac3lbntjhflxlo7m

Histone Deacetylase Inhibition by Sodium Butyrate Chemotherapy Ameliorates the Neurodegenerative Phenotype in Huntington's Disease Mice

Robert J. Ferrante, James K. Kubilus, Junghee Lee, Hoon Ryu, Ayshe Beesen, Birgit Zucker, Karen Smith, Neil W. Kowall, Rajiv R. Ratan, Ruth Luthi-Carter, Steven M. Hersch
2003 Journal of Neuroscience  
Hybridizations and washes were conducted as described previously (Luthi-Carter et al., 2002) .  ...  Gene expression profiling has shown that mutant huntingtin protein selectively affects the pattern of gene expression (Luthi-Carter et al., 2000) .  ... 
doi:10.1523/jneurosci.23-28-09418.2003 pmid:14561870 fatcat:igiuxs3a4re23cer4glw24ai4i
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