Publications by authors named "Sébastien Holbert"

14 Publications

  • Page 1 of 1

Typhimurium Invalidated for the Three Currently Known Invasion Factors Keeps Its Ability to Invade Several Cell Models.

Front Cell Infect Microbiol 2018 10;8:273. Epub 2018 Aug 10.

ISP, Institut National de la Recherche Agronomique (INRA), UMR 1282, Université de Tours, Paris, France.

To establish an infection, has to interact with eukaryotic cells. Invasion of non-phagocytic cells (i.e., epithelial, fibroblast and endothelial cells) involves either a trigger or a zipper mechanism mediated by the T3SS-1 or the invasin Rck, respectively. Another outer membrane protein, PagN, was also implicated in the invasion. However, other unknown invasion factors have been previously suggested. Our goal was to evaluate the invasion capability of a Typhimurium strain invalidated for the three known invasion factors. Non-phagocytic cell lines of several animal origins were tested in a gentamicin protection assay. In most cells, we observed a drastic decrease in the invasion rate between the wild-type and the triple mutant. However, in five cell lines, the triple mutant invaded cells at a similarly high level to the wild-type, suggesting the existence of unidentified invasion factors. For the wild-type and the triple mutant, scanning-electron microscopy, confocal imaging and use of biochemical inhibitors confirmed their cellular uptake and showed a zipper-like mechanism of internalization involving both clathrin- and non-clathrin-dependent pathways. Despite a functional T3SS-1, the wild-type bacteria seemed to use the same entry route as the mutant in our cell model. All together, these results demonstrate the existence of unknown invasion factors, which require further characterization.
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http://dx.doi.org/10.3389/fcimb.2018.00273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6095967PMC
August 2019

Evaluation of mycobacteria-specific gamma interferon and antibody responses before and after a single intradermal skin test in cattle naturally exposed to M. avium subsp. paratuberculosis and experimentally infected with M. bovis.

Vet Immunol Immunopathol 2018 Feb 12;196:35-47. Epub 2017 Dec 12.

Unit "Bacterial Zoonoses of livestock", Operational Direction Bacterial Diseases, Veterinary and Agrochemical Research Center (CODA-CERVA), Groeselenberg, Brussels, Belgium.

This study reports on the diagnostic potential of IFN-γ release assays and serology for Mycobacterium bovis in six naturally M. avium subsp. paratuberculosis (Map) exposed bulls of which four were intratracheally infected with a Belgian field strain of M. bovis. Heparinized blood, serum and fecal samples were collected at regular time intervals for mycobacteria-specific IFN-γ release assays, antibody analysis and for Map culture respectively. Single intradermal skin test (SIT) with bovine tuberculin (PPD-B) was performed on day 115 and animals were sacrificed on day 133 after M. bovis infection. Organs were collected and stored for histopathological examination, modified Ziehl-Neelsen staining and bacteriological analysis of M. bovis and Map by culture and RT-PCR. Prior to infection five animals showed positive IFN-γ responses to avian PPD (PPD-A) and four were positive in Map PCR (IS900) on faeces. Three M. bovis infected animals reacted as early as day 14 with sustained higher PPD-B than PPD-A specific IFN-γ responses, whereas the fourth animal (with the strongest PPD-A response prior to infection) showed sustained higher PPD-B specific IFN-γ levels only a day 56 after infection. Two of the infected animals had a sustained positive IFN-γ response to the ESAT-6/CFP-10/TB7.7 (QuantiFERON-TB Gold) peptide cocktail as early as day 14, among which the animal with the initial high PPD-A response. Later during infection, positive responses were found to ESAT-6 peptides in three infected bulls and to CFP-10 peptides in all four infected bulls. One of the control animals reacted intermittently to the ESAT-6/CFP10/TB7.7 cocktail. Prior to SIT, weak but positive MPB83/MBP70 specific antibody responses were detected in two of the infected bulls. All four M. bovis infected bulls reacted with a positive skin test and showed, as reported by others, increased mycobacteria specific IFN-γ production and increased positive responses in MPB83/MBP70 specific serology after SIT. At autopsy, M. bovis lesions were detected in all four experimentally infected bulls. Our results indicate that in Map exposed cattle, M. bovis diagnosis using IFN-γ assays needs a combination of PPD-B/A and ESAT-6/CFP10 for early and optimal sensitivity and that sensitivity of MPB83/MBP70 serodiagnosis is dramatically increased by prior skin testing. Map exposure did not interfere with the development of SIT in M. bovis infected animals, but resulted in a false positive M. bovis specific IFN-γ and antibody response after SIT in one of the two control animals (which remained negative in skin-test).
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http://dx.doi.org/10.1016/j.vetimm.2017.12.007DOI Listing
February 2018

Experimental infection of cattle with Mycobacterium tuberculosis isolates shows the attenuation of the human tubercle bacillus for cattle.

Sci Rep 2018 01 17;8(1):894. Epub 2018 Jan 17.

UCD School of Veterinary Medicine, University College Dublin, Dublin, Ireland.

The Mycobacterium tuberculosis complex (MTBC) is the collective term given to the group of bacteria that cause tuberculosis (TB) in mammals. It has been reported that M. tuberculosis H37Rv, a standard reference MTBC strain, is attenuated in cattle compared to Mycobacterium bovis. However, as M. tuberculosis H37Rv was isolated in the early 1930s, and genetic variants are known to exist, we sought to revisit this question of attenuation of M. tuberculosis for cattle by performing a bovine experimental infection with a recent M. tuberculosis isolate. Here we report infection of cattle using M. bovis AF2122/97, M. tuberculosis H37Rv, and M. tuberculosis BTB1558, the latter isolated in 2008 during a TB surveillance project in Ethiopian cattle. We show that both M. tuberculosis strains caused reduced gross pathology and histopathology in cattle compared to M. bovis. Using M. tuberculosis H37Rv and M. bovis AF2122/97 as the extremes in terms of infection outcome, we used RNA-Seq analysis to explore differences in the peripheral response to infection as a route to identify biomarkers of progressive disease in contrast to a more quiescent, latent infection. Our work shows the attenuation of M. tuberculosis strains for cattle, and emphasizes the potential of the bovine model as a 'One Health' approach to inform human TB biomarker development and post-exposure vaccine development.
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http://dx.doi.org/10.1038/s41598-017-18575-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5772528PMC
January 2018

An Updated View on the Rck Invasin of : Still Much to Discover.

Front Cell Infect Microbiol 2017 8;7:500. Epub 2017 Dec 8.

Institut National de la Recherche Agronomique, UMR1282 Infectiologie et Santé Publique, Nouzilly, France.

is a facultative intracellular Gram-negative bacterium, responsible for a wide range of food- and water-borne diseases ranging from gastroenteritis to typhoid fever depending on hosts and serotypes. thus represents a major threat to public health. A key step in pathogenesis is the invasion of phagocytic and non-phagocytic host cells. To trigger its own internalization into non-phagocytic cells, has developed different mechanisms, involving several invasion factors. For decades, it was accepted that could only enter cells through a type three secretion system, called T3SS-1. Recent research has shown that this bacterium expresses outer membrane proteins, such as the Rck protein, which is able to induce entry mechanism. Rck mimics natural host cell ligands and triggers engulfment of the bacterium by interacting with the epidermal growth factor receptor. is thus able to use multiple entry pathways during the infection process. However, it is unclear how and when exploits the T3SS-1 and Rck entry mechanisms. As a series of reviews have focused on the T3SS-1, this review aims to describe the current knowledge and the limitations of our understanding of the Rck outer membrane protein. The regulatory cascade which controls Rck expression and the molecular mechanisms underlying Rck-mediated invasion into cells are summarized. The potential role of Rck-mediated invasion in pathogenesis and the intracellular behavior of the bacteria following a Rck-dependent entry are discussed.
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http://dx.doi.org/10.3389/fcimb.2017.00500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5727353PMC
December 2018

Interferon gamma response to Mycobacterium avium subsp. paratuberculosis specific lipopentapeptide antigen L5P in cattle.

Res Vet Sci 2015 Oct 1;102:118-21. Epub 2015 Aug 1.

UMR1282, Infectiologie et Santé Publique (ISP-311), INRA Centre Val de Loire, F-37380 Nouzilly, France. Electronic address:

After Mycobacterium avium subsp. paratuberculosis (Map) infection the cell-mediated immune (CMI) response indicative of early Th1 activation may be detected using interferon-gamma release assay (IGRA). Currently, the purified protein derivatives (PPDs), i.e., the total extract of mycobacteria antigens are used to recall CMI responses against Map. This study aimed to assess the ability of the chemically synthesized Map specific cell wall lipopentapeptide L5P to induce CMI response in cows infected by Map compared to PPD. L5P and PPD elicited an IFN-γ response in 12 and 35 animals from two Map infected herds respectively, but IFN-γ was not detected in the 13 cows recruited from a non-infected herd. Levels of IFN-γ detected were higher with PPD than with L5P. There was no correlation between the IFN-γ response and the humoral response to Map or faecal culture.
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http://dx.doi.org/10.1016/j.rvsc.2015.07.017DOI Listing
October 2015

In silico epitope analysis of unique and membrane associated proteins from Mycobacterium avium subsp. paratuberculosis for immunogenicity and vaccine evaluation.

J Theor Biol 2015 Nov 13;384:1-9. Epub 2015 Aug 13.

Centro de Investigaciones Biológicas del Noroeste, SC. Instituto Politécnico Nacional 195, Playa Palo de Santa Rita Sur, La Paz B.C.S. C.P. 23096, Mexico. Electronic address:

Mycobacterium avium subsp. paratuberculosis (MAP) is the etiologic agent of paratuberculosis disease affecting ruminants worldwide. The aim of this study was to identify potential candidate antigens and epitopes by bio and immuno-informatic tools which could be later evaluated as vaccines and/or diagnosis. 110 protein sequences were selected from MAP K-10 genome database: 48 classified as putative enzymes involved in surface polysaccharide and lipopolysaccharide synthesis, as membrane associated and secreted proteins, 32 as conserved membrane proteins, and 30 as absent from other mycobacterial genomes. These 110 proteins were preliminary screened for Major Histocompatibility Complex (MHC) class II affinity and promiscuity using ProPred program. In addition, subcellular localization and host protein homology was analyzed. From these analyses, 23 MAP proteins were selected for a more accurate inmunoinformatic analysis (i.e. T cell and B cell epitopes analysis) and for homology with mycobacterial proteins. Finally, eleven MAP proteins were identified as potential candidates for further immunogenic evaluation: six proteins (MAP0228c, MAP1239c, MAP2232, MAP3080, MAP3131 and MAP3890) were identified as presenting potential T cell epitopes, while 5 selected proteins (MAP0232c, MAP1240c, MAP1738, MAP2239 and MAP3641c) harbored a large numbers of epitopes predicted to induce both cell- and antibody-mediated immune responses. Moreover, immunogenicity of selected epitopes from MAP1239c were evaluated in IFN-γ release assay. In summary, eleven M. avium subsp. paratuberculosis proteins were identified by in silico analysis and need to be further evaluated for their immunodiagnostic and vaccine potential in field and mice model.
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http://dx.doi.org/10.1016/j.jtbi.2015.08.003DOI Listing
November 2015

KIF1A, an axonal transporter of synaptic vesicles, is mutated in hereditary sensory and autonomic neuropathy type 2.

Am J Hum Genet 2011 Aug 4;89(2):219-30. Epub 2011 Aug 4.

Centre of Excellence in Neuromics, Montréal, Québec, Canada.

Hereditary sensory and autonomic neuropathy type II (HSANII) is a rare autosomal-recessive disorder characterized by peripheral nerve degeneration resulting in a severe distal sensory loss. Although mutations in FAM134B and the HSN2 exon of WNK1 were associated with HSANII, the etiology of a substantial number of cases remains unexplained. In addition, the functions of WNK1/HSN2 and FAM134B and their role in the peripheral nervous system remain poorly understood. Using a yeast two-hybrid screen, we found that KIF1A, an axonal transporter of synaptic vesicles, interacts with the domain encoded by the HSN2 exon. In parallel to this screen, we performed genome-wide homozygosity mapping in a consanguineous Afghan family affected by HSANII and identified a unique region of homozygosity located on chromosome 2q37.3 and spanning the KIF1A gene locus. Sequencing of KIF1A in this family revealed a truncating mutation segregating with the disease phenotype. Subsequent sequencing of KIF1A in a series of 112 unrelated patients with features belonging to the clinical spectrum of ulcero-mutilating sensory neuropathies revealed truncating mutations in three additional families, thus indicating that mutations in KIF1A are a rare cause of HSANII. Similarly to WNK1 mutations, pathogenic mutations in KIF1A were almost exclusively restricted to an alternatively spliced exon. This study provides additional insights into the molecular pathogenesis of HSANII and highlights the potential biological relevance of alternative splicing in the peripheral sensory nervous system.
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http://dx.doi.org/10.1016/j.ajhg.2011.06.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3155159PMC
August 2011

HMSN/ACC truncation mutations disrupt brain-type creatine kinase-dependant activation of K+/Cl- co-transporter 3.

Hum Mol Genet 2008 Sep 19;17(17):2703-11. Epub 2008 Jun 19.

Department of Medicine, Centre of Excellence in Neuromics, CHUM Research Centre, University of Montreal, Montreal, QC, Canada.

The potassium-chloride co-transporter 3 (KCC3) is mutated in hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC); however, the molecular mechanisms of HMSN/ACC pathogenesis and the exact role of KCC3 in the development of the nervous system remain poorly understood. The functional regulation of this transporter by protein partners is also largely unknown. Using a yeast two-hybrid approach, we discovered that the C-terminal domain (CTD) of KCC3, which is lost in most HMSN/ACC-causing mutations, directly interacts with brain-specific creatine kinase (CK-B), an ATP-generating enzyme that is also a partner of KCC2. The interaction of KCC3 with CK-B was further confirmed by in vitro glutathione S-transferase pull-down assay, followed by sequencing of the pulled-down complexes. In transfected cultured cells, immunofluorescence labeling showed that CK-B co-localizes with wild-type KCC3, whereas the kinase fails to interact with the inactive truncated KCC3. Finally, CK-B's inhibition by DNFB results in reduction of activity of KCC3 in functional assays using Xenopus laevis oocytes. This physical and functional association between the co-transporter and CK-B is, therefore, the first protein-protein interaction identified to be potentially involved in the pathophysiology of HMSN/ACC.
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http://dx.doi.org/10.1093/hmg/ddn172DOI Listing
September 2008

Sirtuin inhibition protects from the polyalanine muscular dystrophy protein PABPN1.

Hum Mol Genet 2008 Jul 7;17(14):2108-17. Epub 2008 Apr 7.

INSERM, Laboratory of Neuronal Cell Biology and Pathology, Center for Psychiatry and Neuroscience UMR 894, University of Paris Descartes, Equipe d'accueil 4059, 75014 Paris, France.

Oculopharyngeal muscular dystrophy (OPMD) is caused by polyalanine expansion in nuclear protein PABPN1 [poly(A) binding protein nuclear 1] and characterized by muscle degeneration. Druggable modifiers of proteotoxicity in degenerative diseases, notably the longevity modulators sirtuins, may constitute useful therapeutic targets. However, the modifiers of mutant PABPN1 are unknown. Here, we report that longevity and cell metabolism modifiers modulate mutant PABPN1 toxicity in the muscle cell. Using PABPN1 nematodes that show muscle cell degeneration and abnormal motility, we found that increased dosage of the sirtuin and deacetylase sir-2.1/SIRT1 exacerbated muscle pathology, an effect dependent on the transcription factor daf-16/FoxO and fuel sensor aak-2/AMPK (AMP-activated protein kinase), while null mutants of sir-2.1, daf-16 and aak-2 were protective. Consistently, the Sir2 inhibitor sirtinol was protective, whereas the Sir2 and AMPK activator resveratrol was detrimental. Furthermore, rescue by sirtinol was dependent on daf-16 and not aak-2, whereas aggravation by resveratrol was dependent on aak-2 and not daf-16. Finally, the survival of mammalian cells expressing mutant PABPN1 was promoted by sirtinol and decreased by resveratrol. Altogether, our data identify Sir2 and AMPK inhibition as therapeutic strategies for muscle protection in OPMD, extending the value of druggable proteins in cell maintenance networks to polyalanine diseases.
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http://dx.doi.org/10.1093/hmg/ddn109DOI Listing
July 2008

Polyalanine expansion mutations in the X-linked hypopituitarism gene SOX3 result in aggresome formation and impaired transactivation.

Front Biosci 2007 Jan 1;12:2085-95. Epub 2007 Jan 1.

Pituitary Research Unit, Murdoch Childrens Research Institute, Royal Childrens Hospital, Melbourne, Australia.

Polyalanine expansion mutations have been identified in eight transcription factors that are associated with a range of congenital disorders. While some of these mutant proteins have been shown to generate cellular aggregates in heterologous cell lines, little is known about the mechanism by which these aggregates cause disease. Here we examine the aggregation and functional properties of the two known polyalanine expansion mutations associated with X-linked Hypopituitarism (XH), SOX3(22Ala) and SOX3(26Ala), which contain an additional seven and eleven alanine residues, respectively. SOX3(22Ala) and SOX3(26Ala) proteins form cytoplasmic aggregates and nuclear inclusions in transiently transfected COS-7 and CHO K1 cells, and in transfected explant cultures of chick neural epithelium. SOX3(26Ala) exhibits a more potent aggregation phenotype, resulting in significantly more cells with dispersed cytoplasmic and large perinuclear aggregates. SOX3(22Ala) and SOX3(26Ala) protein aggregates exhibit the key properties of aggresomes including vimentin redistribution, colocalisation with the Microtubule Organising Centre and sensitivity to microtubule disruption. This is the first time that aggresomes have been implicated in the aetiology of a polyalanine expansion disorder, suggesting that XH and protein conformation disorders may become manifest through similar pathological mechanisms. Further, we show that mutant SOX3 proteins have impaired transcriptional activity and reduced capacity to inhibit beta-catenin/TCF-mediated transcription. These data suggest that deregulation of SOX3 target genes and inappropriate canonical Wnt signaling in central nervous system (CNS) progenitors may also contribute to dysfunction of the hypothalamic-pituitary axis in XH patients.
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http://dx.doi.org/10.2741/2213DOI Listing
January 2007

Association of a functional deficit of the BKCa channel, a synaptic regulator of neuronal excitability, with autism and mental retardation.

Am J Psychiatry 2006 Sep;163(9):1622-9

INSERM U619 Génétique de l'autisme et des déficiences mentales, Laboratoire de Génétique chromosomique, CHR La Source-BP86709-45067 Orléans cedex 2, France.

Objective: Autism is a complex, largely genetic psychiatric disorder. In the majority of cases, the cause of autism is not known, but there is strong evidence for a genetic etiology. To identify candidate genes, the physical mapping of balanced chromosomal aberrations is a powerful strategy, since several genes have been characterized in numerous disorders. In this study, the authors analyzed a balanced reciprocal translocation arising de novo in a subject with autism and mental retardation.

Method: The authors performed the physical mapping of the balanced 9q23/10q22 translocation by fluorescent in situ hybridization experiments using bacterial artificial chromosome clones covering the areas of interest.

Results: Findings revealed that the KCNMA1 gene, which encodes the alpha-subunit of the large conductance Ca(2+)-activated K(+) (BK(Ca)) channel, a synaptic regulator of neuronal excitability, is physically disrupted. Further molecular and functional analyses showed the haploinsufficiency of this gene as well as decreased activity of the coded BK(Ca )channel. This activity can be enhanced in vitro by addition of a BK(Ca )channel opener (BMS-204352). Further mutational analyses on 116 autistic subjects led to the identification of an amino acid substitution located in a highly conserved domain of the protein not found in comparison subjects.

Conclusions: These results suggest a possible association between a functional defect of the BK(Ca) channel and autistic disorder and raise the hypothesis that deficits in synaptic transmission may contribute to the physiopathology of autism and mental deficiency.
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http://dx.doi.org/10.1176/ajp.2006.163.9.1622DOI Listing
September 2006

CA150 expression delays striatal cell death in overexpression and knock-in conditions for mutant huntingtin neurotoxicity.

J Neurosci 2006 Apr;26(17):4649-59

Avenir Group, Laboratory of Genomic Biology, Institut National de la Santé et de la Recherche Médicale, 75014 Paris, France.

Transcriptional dysregulation caused by expanded polyglutamines (polyGlns) in huntingtin (htt) may be central to cell-autonomous mechanisms for neuronal cell death in Huntington's disease (HD) pathogenesis. We hypothesized that these mechanisms may involve the dysfunction of the transcriptional regulator CA150, a putative modifier of onset age in HD, because it binds to htt and accumulates in an HD grade-dependent manner in striatal and cortical neurons. Consistently, we report herein that CA150 expression rescues striatal cell death in lentiviral overexpression (rats) and knock-in (mouse cells) conditions for mutant htt neurotoxicity. In both systems, rescue was dependent on the (Gln-Ala)38 repeat normally found in CA150. We excluded the possibility that rescue may be caused by the (Gln-Ala)38 repeat interacting with polyGlns and, by doing so, blocking mutant htt toxicity. In contrast, we found the (Gln-Ala)38 repeat is required for the nuclear restriction of exogenous CA150, suggesting that rescue requires nuclear CA150. Additionally, we found the (Gln-Ala)38 repeat was dispensable for CA150 transcriptional repression ability, suggesting further that CA150 localization is critical to rescue. Finally, rescue was associated with increased neuritic aggregation, with no reduction of nuclear inclusions, suggesting the solubilization and nuclear export of mutant htt. Together, our data indicate that mutant htt may induce CA150 dysfunction in striatal neurons and suggest that the restoration of nuclear protein cooperativity may be neuroprotective.
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http://dx.doi.org/10.1523/JNEUROSCI.5409-05.2006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6674076PMC
April 2006

Genetic and pharmacological suppression of polyglutamine-dependent neuronal dysfunction in Caenorhabditis elegans.

J Mol Neurosci 2004 ;23(1-2):61-8

Laboratory of Genomic Biology, Inserm Avenir Group, Centre Paul Broca, 75014 Paris, France.

The identification of disease genes for several neurodegenerative illnesses has allowed for the development of disease models in experimental organisms. We discuss our approach to studying Huntington's disease, the best characterized of the polyglutamine (polyQ) expansion disorders. We have developed a system in Caenorhabditis elegans to study the effects of (polyQ)-dependent neuronal dysfunction at the resolution of two neurons in screening for genetic and pharmacological suppression. Our data suggest that C. elegans might be instructive in searching for targets and active compounds against polyglutamine neuronal toxicity.
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http://dx.doi.org/10.1385/JMN:23:1-2:061DOI Listing
September 2004

Cdc42-interacting protein 4 binds to huntingtin: neuropathologic and biological evidence for a role in Huntington's disease.

Proc Natl Acad Sci U S A 2003 Mar 25;100(5):2712-7. Epub 2003 Feb 25.

Laboratory of Genomic Biology, Institut National de la Santé et de la Recherche Médicale-Avenir Group and Fondation Jean Dausset-Centre d'Etude du Polymorphisme Humain, 75010 Paris, France.

Huntington's disease (HD) is a neurodegenerative disease caused by polyglutamine (polyQ) expansion in the protein huntingtin (htt). Pathogenesis in HD seems to involve the formation of neuronal intranuclear inclusions and the abnormal regulation of transcription and signal transduction. To identify previously uncharacterized htt-interacting proteins in a simple model system, we used a yeast two-hybrid screen with a Caenorhabditis elegans activation domain library. We found a predicted SH3 domain protein (K08E3.3b) that interacts with N-terminal htt in two-hybrid tests. A human homolog of K08E3.3b is the Cdc42-interacting protein 4 (CIP4), a protein involved in Cdc42 and Wiskott-Aldrich syndrome protein-dependent signal transduction. CIP4 interacted in vitro with full-length htt from lymphoblastoid cells. Neuronal CIP4 immunoreactivity increased with neuropathological severity in the neostriatum of HD patients and partially colocalized to ubiquitin-positive aggregates. Marked CIP4 overexpression also was observed in Western blot from human HD brain striatum. The overexpression of CIP4 induced the death of striatal neurons. Our data suggest that CIP4 accumulation and cellular toxicity may have a role in HD pathogenesis.
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http://dx.doi.org/10.1073/pnas.0437967100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC151406PMC
March 2003