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Anna-elina Lehesjoki - One of the best experts on this subject based on the ideXlab platform.
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Quantitative Changes in the Mitochondrial Proteome of CereBellar Synaptosomes From Preclinical <B>CystatinB> B-Deficient Mice.
Frontiers in molecular neuroscience, 2020Co-Authors: Katarin Gorski, Albert Spoljaric, Tuula A. Nyman, Kai Kaila, Brendan J. Battersby, Anna-elina LehesjokiAbstract:Progressive myoclonus epilepsy of Unverricht-LundBorg type (EPM1) is a neurodegenerative disorder caused By loss-of-function mutations in the <B>CystatinB> B (CSTB) gene. Progression of the clinical symptoms in EPM1 patients, including stimulus-sensitive myoclonus, tonic-clonic seizures, and ataxia, are well descriBed. However, the cellular dysfunction during the presymptomatic phase that precedes the disease onset is not understood. CSTB deficiency leads to alterations in GABAergic signaling, and causes early neuroinflammation followed By progressive neurodegeneration in Brains of a mouse model, manifesting as progressive myoclonus and ataxia. Here, we report the first proteome atlas from cereBellar synaptosomes of presymptomatic CstB-deficient mice, and propose that early mitochondrial dysfunction is important to the pathogenesis of altered synaptic function in EPM1. A decreased sodium- and chloride dependent GABA transporter 1 (GAT-1) aBundance was noted in synaptosomes with CSTB deficiency, But no functional difference was seen Between the two genotypes in electrophysiological experiments with pharmacological Block of GAT-1. Collectively, our findings provide novel insights into the early onset and pathogenesis of CSTB deficiency, and reveal greater complexity to the molecular pathogenesis of EPM1.
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Impaired osteoclast homeostasis in the <B>CystatinB> B-deficient mouse model of progressive myoclonus epilepsy
Bone reports, 2015Co-Authors: Otto Manninen, Tiina Laitala-leinonen, Outi Kopra, Tero Puolakkainen, Jemina Lehto, Elina Harittu, Aki Kallonen, Marko Peura, Riku Kiviranta, Anna-elina LehesjokiAbstract:ABstract Progressive myoclonus epilepsy of Unverricht–LundBorg type (EPM1) is an autosomal recessively inherited disorder characterized By incapacitating stimulus-sensitive myoclonus and tonic-clonic epileptic seizures with onset at the age of 6 to 16 years. EPM1 patients also exhiBit a range of skeletal changes, e.g., thickened frontal cranial Bone, arachnodactyly and scoliosis. Mutations in the gene encoding <B>CystatinB> B (CSTB) underlie EPM1. CSTB is an inhiBitor of cysteine cathepsins, including cathepsin K, a key enzyme in Bone resorption By osteoclasts. CSTB has previously Been shown to protect osteoclasts from experimentally induced apoptosis and to modulate Bone resorption in vitro. Nevertheless, its physiological function in Bone and the cause of the Bone changes in patients remain unknown. Here we used the CSTB-deficient mouse ( CstB −/− ) model of EPM1 to evaluate the contriBution of defective CSTB protein function on Bone pathology and osteoclast differentiation and function. Micro-computed tomography of hind limBs revealed thicker traBeculae and elevated Bone mineral density in the traBecular Bone of CstB −/− mice. Histology from CstB −/− mouse Bones showed lower osteoclast count and thinner growth plates in long Bones. Bone marrow-derived osteoclast cultures revealed lower osteoclast numBer and size in the CstB −/− group. CstB −/− osteoclasts formed less and smaller resorption pits in an in vitro assay. This impaired resorptive capacity was likely due to a decrease in osteoclast numBers and size. These data imply that the skeletal changes in CstB −/− mice and in EPM1 patients are a result of CSTB deficiency leading to impaired osteoclast formation and consequently compromised resorptive capacity. These results suggest that the role of CSTB in osteoclast homeostasis and modulation of Bone metaBolism extends Beyond cathepsin K regulation.
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Progressive volume loss and white matter degeneration in cstB-deficient mice: a diffusion tensor and longitudinal volumetry MRI study.
PloS one, 2014Co-Authors: Otto Manninen, Saara Tegelberg, Anna-elina Lehesjoki, Kimmo K. Lehtimäki, Teemu Laitinen, Olli Gröhn, Outi KopraAbstract:Unverricht-LundBorg type progressive myoclonus epilepsy (EPM1, OMIM 254800) is an autosomal recessive disorder characterized By onset at the age of 6 to 16 years, incapacitating stimulus-sensitive myoclonus and tonic-clonic epileptic seizures. It is caused By mutations in the gene encoding <B>CystatinB> B. Previously, widespread white matter changes and atrophy has Been detected Both in adult EPM1 patients and in 6-month-old <B>CystatinB> B-deficient mice, a mouse model for the EPM1 disease. In order to elucidate the spatiotemporal dynamics of the Brain atrophy and white matter changes in EPM1, we conducted longitudinal in vivo magnetic resonance imaging and ex vivo diffusion tensor imaging accompanied with tract-Based spatial statistics analysis to compare volumetric changes and fractional anisotropy in the Brains of 1 to 6 months of age <B>CystatinB> B-deficient and control mice. The results reveal progressive But non-uniform volume loss of the <B>CystatinB> B-deficient mouse Brains, indicating that different neuronal populations possess distinct sensitivity to the damage caused By <B>CystatinB> B deficiency. The diffusion tensor imaging data reveal early and progressive white matter alterations in <B>CystatinB> B-deficient mice affecting all major tracts. The results also indicate that the white matter damage in the <B>CystatinB> B-deficient Brain is most likely secondary to glial activation and neurodegenerative events rather than a primary result of CSTB deficiency. The data also show that diffusion tensor imaging comBined with TBSS analysis provides a feasiBle approach not only to follow white matter damage in neurodegenerative mouse models But also to detect fractional anisotropy changes related to normal white matter maturation and reorganisation.
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Thickened skull, scoliosis and other skeletal findings in Unverricht-LundBorg disease link <B>CystatinB> B function to Bone metaBolism.
Bone, 2012Co-Authors: Sanna Suoranta, Anna-elina Lehesjoki, Hannu Manninen, Päivi Koskenkorva, Mervi Könönen, Rita Laitinen, Reetta Kälviäinen, Ritva VanninenAbstract:ABstract Purpose Unverricht–LundBorg disease (EPM1) is a rare type of inherited progressive myoclonic epilepsy resulting from mutations in the <B>CystatinB> B gene, CSTB , which encodes a cysteine cathepsin inhiBitor. <B>CystatinB> B, cathepsin K, and altered osteoclast Bone resorption activity are interconnected in vitro. This study evaluated the skeletal characteristics of patients with EPM1. Methods Sixty-six genetically verified EPM1 patients and 50 healthy controls underwent head MRI. Skull dimensions and regional calvarial thickness was measured perpendicular to each calvarial Bone from T1-weighted 3-dimensional images using multiple planar reconstruction tools. All clinical X-ray files of EPM1 patients were collected and reviewed By an experienced radiologist. A total of 337 X-ray studies were analyzed, and non-traumatic structural anomalies, dysplasias and deformities were registered. Results EPM1 patients exhiBited significant thickening in all measured cranial Bones compared to healthy controls. The mean skull thickness was 10.0 ± 2.0 mm in EPM1 patients and 7.6 ± 1.2 mm in healthy controls (p Conclusions Skull thickening and an increased prevalence of aBnormal findings in skeletal radiographs of patients with EPM1 suggest that this condition is connected to defective <B>CystatinB> B function. These findings further emphasize the role of <B>CystatinB> B in Bone metaBolism in humans.
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Thickened skull, scoliosis and other skeletal findings in Unverricht-LundBorg disease elucidate the role of <B>CystatinB> B gene as an intracellular modulator of Bone resorption in humans
2012Co-Authors: Sanna Suoranta, Anna-elina Lehesjoki, Hannu Manninen, Päivi Koskenkorva, Mervi Könönen, Reetta Kälviäinen, Ritva VanninenAbstract:Poster: "ECR 2012 / C-1120 / Thickened skull, scoliosis and other skeletal findings in Unverricht-LundBorg disease elucidate the role of <B>CystatinB> B gene as an intracellular modulator of Bone resorption in humans" By: "S. Suoranta1, H. Manninen1, P. Koskenkorva1, M. Kononen1, R. Kalviainen1, A.-E. Lehesjoki2, R. Vanninen1; 1Kuopio/FI, 2Helsinki/FI"
Reetta Kälviäinen - One of the best experts on this subject based on the ideXlab platform.
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White Matter Degeneration with Unverricht-LundBorg Progressive Myoclonus Epilepsy: A Translational Diffusion-Tensor Imaging Study in Patients and <B>CystatinB> B–Deficient Mice
Radiology, 2013Co-Authors: Otto Manninen, Outi Kopra, Päivi Koskenkorva, Mervi Könönen, Reetta Kälviäinen, Kimmo K. Lehtimäki, Jelena Hyppönen, Teemu Laitinen, Hannu Kalimo, Olli GröhnAbstract:Tract-Based spatial statistics showed degeneration in the suBcortical white matter, thalamocortical system, and cereBellum in patients with Unverricht-LundBorg progressive myoclonus epilepsy and <B>CystatinB> B–deficient mice, which suggests that the principally cortical motor disturBances and other symptoms also involve the thalamocortical system and cereBellum.
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Thickened skull, scoliosis and other skeletal findings in Unverricht-LundBorg disease link <B>CystatinB> B function to Bone metaBolism.
Bone, 2012Co-Authors: Sanna Suoranta, Anna-elina Lehesjoki, Hannu Manninen, Päivi Koskenkorva, Mervi Könönen, Rita Laitinen, Reetta Kälviäinen, Ritva VanninenAbstract:ABstract Purpose Unverricht–LundBorg disease (EPM1) is a rare type of inherited progressive myoclonic epilepsy resulting from mutations in the <B>CystatinB> B gene, CSTB , which encodes a cysteine cathepsin inhiBitor. <B>CystatinB> B, cathepsin K, and altered osteoclast Bone resorption activity are interconnected in vitro. This study evaluated the skeletal characteristics of patients with EPM1. Methods Sixty-six genetically verified EPM1 patients and 50 healthy controls underwent head MRI. Skull dimensions and regional calvarial thickness was measured perpendicular to each calvarial Bone from T1-weighted 3-dimensional images using multiple planar reconstruction tools. All clinical X-ray files of EPM1 patients were collected and reviewed By an experienced radiologist. A total of 337 X-ray studies were analyzed, and non-traumatic structural anomalies, dysplasias and deformities were registered. Results EPM1 patients exhiBited significant thickening in all measured cranial Bones compared to healthy controls. The mean skull thickness was 10.0 ± 2.0 mm in EPM1 patients and 7.6 ± 1.2 mm in healthy controls (p Conclusions Skull thickening and an increased prevalence of aBnormal findings in skeletal radiographs of patients with EPM1 suggest that this condition is connected to defective <B>CystatinB> B function. These findings further emphasize the role of <B>CystatinB> B in Bone metaBolism in humans.
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Thickened skull, scoliosis and other skeletal findings in Unverricht-LundBorg disease elucidate the role of <B>CystatinB> B gene as an intracellular modulator of Bone resorption in humans
2012Co-Authors: Sanna Suoranta, Anna-elina Lehesjoki, Hannu Manninen, Päivi Koskenkorva, Mervi Könönen, Reetta Kälviäinen, Ritva VanninenAbstract:Poster: "ECR 2012 / C-1120 / Thickened skull, scoliosis and other skeletal findings in Unverricht-LundBorg disease elucidate the role of <B>CystatinB> B gene as an intracellular modulator of Bone resorption in humans" By: "S. Suoranta1, H. Manninen1, P. Koskenkorva1, M. Kononen1, R. Kalviainen1, A.-E. Lehesjoki2, R. Vanninen1; 1Kuopio/FI, 2Helsinki/FI"
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unstaBle insertion in the 5 flanking region of the <B>CystatinB> B gene is the most common mutation in progressive myoclonus epilepsy type 1 epm1
Nature Genetics, 1997Co-Authors: Ronald G. Lafrenière, Reetta Kälviäinen, Daniel Rochefort, Nathalie Chretien, Johanna M. Rommens, Jeffrey I. Cochius, Unto Nousiainen, George Patry, Kevin Farrell, Birgitta SöderfeldtAbstract:Progressive myoclonus epilepsy type 1 (EPM1, also known as Unverricht-LundBorg disease) is an autosomal recessive disorder characterized By progressively worsening myoclonic jerks, frequent generalized tonic-clonic seizures, and a slowly progressive decline in cognition1. Recently, two mutations in the <B>CystatinB> B gene (also known as stefin B, STFB) mapping to 21q22.3 have Been implicated in the EPM1 phenotype: a G→C suBstitution in the last nucleotide of intron 1 that was predicted to cause a splicing defect in one family, and a C→T suBstitution that would change an Arg codon (CGA) to a stop codon (TGA) at amino acid position 68, resulting in a truncated <B>CystatinB> B protein in two other families2. A fourth family showed undetectaBle amounts of STFB mRNA By northern Blot analysis in an affected individual. We present haplotype and mutational analyses of our collection of 20 unrelated EPM1 patients and families from different ethnic groups. We identify four different mutations, the most common of which consists of an unstaBle ∼600–900 Bp insertion which is resistant to PCR amplification. This insertion maps to a 12-Bp polymorphic tandem repeat located in the 5' flanking region of the STFB gene, in the region of the promoter. The size of the insertion varies Between different EPM1 chromosomes sharing a common haplotype and a common origin, suggesting some level of meiotic instaBility over the course of many generations. This dynamic mutation, which appears distinct from conventional trinucleotide repeat expansions, may arise via a novel mechanism related to the instaBility of tandemly repeated sequences.
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UnstaBle insertion in the 5′ flanking region of the <B>CystatinB> B gene is the most common mutation in progressive myoclonus epilepsy type 1, EPM1
Nature genetics, 1997Co-Authors: Ronald G. Lafrenière, Reetta Kälviäinen, Daniel Rochefort, Nathalie Chretien, Johanna M. Rommens, Jeffrey I. Cochius, Unto Nousiainen, George Patry, Kevin Farrell, Birgitta SöderfeldtAbstract:Progressive myoclonus epilepsy type 1 (EPM1, also known as Unverricht-LundBorg disease) is an autosomal recessive disorder characterized By progressively worsening myoclonic jerks, frequent generalized tonic-clonic seizures, and a slowly progressive decline in cognition1. Recently, two mutations in the <B>CystatinB> B gene (also known as stefin B, STFB) mapping to 21q22.3 have Been implicated in the EPM1 phenotype: a G→C suBstitution in the last nucleotide of intron 1 that was predicted to cause a splicing defect in one family, and a C→T suBstitution that would change an Arg codon (CGA) to a stop codon (TGA) at amino acid position 68, resulting in a truncated <B>CystatinB> B protein in two other families2. A fourth family showed undetectaBle amounts of STFB mRNA By northern Blot analysis in an affected individual. We present haplotype and mutational analyses of our collection of 20 unrelated EPM1 patients and families from different ethnic groups. We identify four different mutations, the most common of which consists of an unstaBle ∼600–900 Bp insertion which is resistant to PCR amplification. This insertion maps to a 12-Bp polymorphic tandem repeat located in the 5' flanking region of the STFB gene, in the region of the promoter. The size of the insertion varies Between different EPM1 chromosomes sharing a common haplotype and a common origin, suggesting some level of meiotic instaBility over the course of many generations. This dynamic mutation, which appears distinct from conventional trinucleotide repeat expansions, may arise via a novel mechanism related to the instaBility of tandemly repeated sequences.
L. M. Meléndez - One of the best experts on this subject based on the ideXlab platform.
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<B>CystatinB> B and HIV regulate the STAT-1 signaling circuit in HIV-infected and INF-β-treated human macrophages.
Journal of neurovirology, 2016Co-Authors: L. E. Rivera, Edmundo Kraiselburd, L. M. MeléndezAbstract:<B>CystatinB> B is a cysteine protease inhiBitor that induces HIV replication in monocyte-derived macrophages (MDM). This protein interacts with signal transducer and activator of transcription (STAT-1) factor and inhiBits the interferon (IFN-β) response in Vero cells By preventing STAT-1 translocation to the nucleus. <B>CystatinB> B also decreases the levels of tyrosine-phosphorylated STAT-1 (STAT-1PY). However, the mechanisms of <B>CystatinB> B regulation on STAT-1 phosphorylation in MDM are unknown. We hypothesized that <B>CystatinB> B inhiBits IFN-β antiviral responses and induces HIV replication in macrophage reservoirs through the inhiBition of STAT-1 phosphorylation. Macrophages were transfected with <B>CystatinB> B siRNA prior to interferon-β treatment or infected with HIV-ADA to determine the effect of <B>CystatinB> B modulation in STAT-1 localization and activation using immunofluorescence and proximity ligation assays. <B>CystatinB> B decreased STAT-1PY and its transportation to the nucleus, while HIV infection retained unphosphorylated STAT (USTAT-1) in the nucleus avoiding its exit to the cytoplasm for eventual phosphorylation. In IFN-β-treated MDM, <B>CystatinB> B inhiBited the nuclear translocation of Both, USTAT-1 and STAT-1PY. These results demonstrate that <B>CystatinB> B interferes with the STAT-1 signaling and IFN-β-antiviral responses perpetuating HIV in macrophage reservoirs.
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Macrophage Derived <B>CystatinB> B/Cathepsin B in HIV Replication and Neuropathogenesis
Current HIV research, 2014Co-Authors: Linda E. Rivera, Krystal Colón, Yisel M. Cantres-rosario, Frances Zenón, L. M. MeléndezAbstract:Mononuclear phagocytes including monocytes and macrophages, are important defense components of innate immunity, But can Be detrimental in HIV-1 infection By serving as the principal reservoirs of virus in Brain and triggering a strong immune response. These viral reservoirs represent a challenge to HIV-1 eradication since they continue producing virus in tissue despite antiretroviral therapy. HIV-1 associated neurocognitive disorders (HAND) involve alterations to the Blood-Brain Barrier and migration of activated HIV-1 infected monocytes to the Brain with suBsequent induced immune activation response. Our group recently showed that HIV replication in monocyte-derived macrophages is associated with increased <B>CystatinB> B. This cysteine protease inhiBitor also inhiBits the interferon-induced antiviral response By decreasing levels of tyrosine phosphorylated STAT-1. These recent discoveries reveal novel mechanisms of HIV persistence that could Be targeted By new therapeutic approaches to eliminate HIV in macrophage reservoirs. However, <B>CystatinB> B has Been also associated with neuroprotection. <B>CystatinB> B is an inhiBitor of the cysteine protease cathepsin B, a potent neurotoxin. During HIV-1 infection <B>CystatinB> B and cathepsin B are upregulated in macrophages. Reduction in <B>CystatinB>/cathepsin interactions in infected macrophages leads to increased cathepsin B secretion and activity which contriButes to neuronal apoptosis. Increased intracellular expression of Both proteins was recently found in monocytes from Hispanic women with HAND. These findings provide new evidence for the role of cathepsin /<B>CystatinB> system in the neuropathogenesis induced By HIV-infected macrophages. We summarize recent research on <B>CystatinB> B and one of its suBstrates, cathepsin B, in HIV replication in macrophages and neuropathogenesis.
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cathepsin B and <B>CystatinB> B in hiv seropositive women are associated with infection and hiv 1 associated neurocognitive disorders
AIDS, 2013Co-Authors: Yisel M Cantresrosario, Marines Plaudvalentin, Yamil Gerena, Richard L Skolasky, Valerie Wojna, L. M. MeléndezAbstract:OBjective: HIV-1-associated neurocognitive disorders (HAND) is triggered By immune activation of Brain cells and remain prevalent during progressive viral infection despite antiretroviral therapy. Cathepsins and <B>CystatinB>s are lysosomal proteins secreted By macrophages and microglia, and may play important roles in neuroregulatory responses.OurlaBoratoryhasshownincreasedsecretionandneurotoxicityofcathepsin Bfrom in-vitroHIV-infected monocyte-derivedmacrophages,and increased expression in postmortem Brain tissue with HIV encephalitis and HAND. We hypothesized that <B>CystatinB> B and cathepsin B could represent potential Biomarkers for HAND. Methods: Monocytes, plasma, and cereBrospinal fluid (CSF) from retrospective samples from 63 HIV-seropositive Hispanic women were selected for this study. These were stratified as 27 normal, 14 asymptomatic, and 22 HIV dementia, and as 14 progressors and 17 nonprogressors. Samples were evaluated for <B>CystatinB>s B and C and cathepsin B expression and activity. Results: Increased cathepsin B and <B>CystatinB>s B and C were found in plasma of HIVseropositive women. Higher intracellular expression of cathepsin B and <B>CystatinB> B were found in monocytes from women with HIV-associated dementia (P <0.05). Significant increase in <B>CystatinB> B concentration in CSF was found in women with dementia compared with HIV-seropositive asymptomatic women. Conclusion: These results demonstrate that dysregulation of <B>CystatinB> B‐cathepsin B system is operative in HIV-associated neurocognitive impairment and suggests that intracellular expression of <B>CystatinB> B and cathepsin B in monocytes could Be potential candidate Biomarkers for HIV dementia, whereas increased cathepsin B and <B>CystatinB>s B and C in plasma are potential candidate markers of chronic HIV-1 activation. 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins AIDS 2013, 27:347‐356
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Cathepsin B and <B>CystatinB> B in HIV-seropositive women are associated with infection and HIV-1-associated neurocognitive disorders
AIDS (London England), 2013Co-Authors: Yisel M. Cantres-rosario, Yamil Gerena, Richard L Skolasky, Valerie Wojna, Marines Plaud-valentin, L. M. MeléndezAbstract:OBjective: HIV-1-associated neurocognitive disorders (HAND) is triggered By immune activation of Brain cells and remain prevalent during progressive viral infection despite antiretroviral therapy. Cathepsins and <B>CystatinB>s are lysosomal proteins secreted By macrophages and microglia, and may play important roles in neuroregulatory responses.OurlaBoratoryhasshownincreasedsecretionandneurotoxicityofcathepsin Bfrom in-vitroHIV-infected monocyte-derivedmacrophages,and increased expression in postmortem Brain tissue with HIV encephalitis and HAND. We hypothesized that <B>CystatinB> B and cathepsin B could represent potential Biomarkers for HAND. Methods: Monocytes, plasma, and cereBrospinal fluid (CSF) from retrospective samples from 63 HIV-seropositive Hispanic women were selected for this study. These were stratified as 27 normal, 14 asymptomatic, and 22 HIV dementia, and as 14 progressors and 17 nonprogressors. Samples were evaluated for <B>CystatinB>s B and C and cathepsin B expression and activity. Results: Increased cathepsin B and <B>CystatinB>s B and C were found in plasma of HIVseropositive women. Higher intracellular expression of cathepsin B and <B>CystatinB> B were found in monocytes from women with HIV-associated dementia (P
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InhiBition of interferon response By <B>CystatinB> B: implication in HIV replication of macrophage reservoirs
Journal of NeuroVirology, 2012Co-Authors: L. Rivera-rivera, J. Perez--laspiur, Krystal Colón, L. M. MeléndezAbstract:<B>CystatinB> B and signal transducer and activator of transcription-1 (STAT-1) phosphorylation have recently Been shown to increase human immunodeficiency virus-1 (HIV-1) replication in monocyte-derived macrophages (MDM), But the molecular pathways By which they do are unknown. We hypothesized that <B>CystatinB> B inhiBits the interferon (IFN) response and regulates STAT-1 phosphorylation By interacting with additional proteins. To test if <B>CystatinB> B inhiBits the IFN-β response, we performed luciferase reporter gene assays in Vero cells, which are IFN deficient. Interferon-stimulated response element (ISRE)-driven expression of firefly luciferase was significantly inhiBited in Vero cells transfected with a <B>CystatinB> B expression vector compared to cells transfected with an empty vector. To determine whether <B>CystatinB> B interacts with other key players regulating STAT-1 phosphorylation and HIV-1 replication, <B>CystatinB> B was immunoprecipitated from HIV-1-infected MDM. The protein complex was analyzed By liquid chromatography tandem mass spectrometry. Protein interactions with <B>CystatinB> B were verified By Western Blots and immunofluorescence with confocal imaging. Our findings confirmed that <B>CystatinB> B interacts with pyruvate kinase M2 isoform, a protein previously associated cocaine enhancement of HIV-1 replication, and major vault protein (MVP), an IFN-responsive protein that interferes with JAK/STAT signals. Western Blot studies confirmed the interaction with pyruvate kinase M2 isoform and MVP. Immunofluorescence studies of HIV-1-infected MDM showed that upregulated MVP colocalized with STAT-1. To our knowledge, the current study is the first to demonstrate the coexpression of <B>CystatinB> B, STAT-1, MVP, and pyruvate kinase M2 isoform with HIV-1 replication in MDM and thus suggests novel targets for HIV-1 restriction in macrophages, the principal reservoirs for HIV-1 in the central nervous system.
Outi Kopra - One of the best experts on this subject based on the ideXlab platform.
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Impaired osteoclast homeostasis in the <B>CystatinB> B-deficient mouse model of progressive myoclonus epilepsy
Bone reports, 2015Co-Authors: Otto Manninen, Tiina Laitala-leinonen, Outi Kopra, Tero Puolakkainen, Jemina Lehto, Elina Harittu, Aki Kallonen, Marko Peura, Riku Kiviranta, Anna-elina LehesjokiAbstract:ABstract Progressive myoclonus epilepsy of Unverricht–LundBorg type (EPM1) is an autosomal recessively inherited disorder characterized By incapacitating stimulus-sensitive myoclonus and tonic-clonic epileptic seizures with onset at the age of 6 to 16 years. EPM1 patients also exhiBit a range of skeletal changes, e.g., thickened frontal cranial Bone, arachnodactyly and scoliosis. Mutations in the gene encoding <B>CystatinB> B (CSTB) underlie EPM1. CSTB is an inhiBitor of cysteine cathepsins, including cathepsin K, a key enzyme in Bone resorption By osteoclasts. CSTB has previously Been shown to protect osteoclasts from experimentally induced apoptosis and to modulate Bone resorption in vitro. Nevertheless, its physiological function in Bone and the cause of the Bone changes in patients remain unknown. Here we used the CSTB-deficient mouse ( CstB −/− ) model of EPM1 to evaluate the contriBution of defective CSTB protein function on Bone pathology and osteoclast differentiation and function. Micro-computed tomography of hind limBs revealed thicker traBeculae and elevated Bone mineral density in the traBecular Bone of CstB −/− mice. Histology from CstB −/− mouse Bones showed lower osteoclast count and thinner growth plates in long Bones. Bone marrow-derived osteoclast cultures revealed lower osteoclast numBer and size in the CstB −/− group. CstB −/− osteoclasts formed less and smaller resorption pits in an in vitro assay. This impaired resorptive capacity was likely due to a decrease in osteoclast numBers and size. These data imply that the skeletal changes in CstB −/− mice and in EPM1 patients are a result of CSTB deficiency leading to impaired osteoclast formation and consequently compromised resorptive capacity. These results suggest that the role of CSTB in osteoclast homeostasis and modulation of Bone metaBolism extends Beyond cathepsin K regulation.
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Progressive volume loss and white matter degeneration in cstB-deficient mice: a diffusion tensor and longitudinal volumetry MRI study.
PloS one, 2014Co-Authors: Otto Manninen, Saara Tegelberg, Anna-elina Lehesjoki, Kimmo K. Lehtimäki, Teemu Laitinen, Olli Gröhn, Outi KopraAbstract:Unverricht-LundBorg type progressive myoclonus epilepsy (EPM1, OMIM 254800) is an autosomal recessive disorder characterized By onset at the age of 6 to 16 years, incapacitating stimulus-sensitive myoclonus and tonic-clonic epileptic seizures. It is caused By mutations in the gene encoding <B>CystatinB> B. Previously, widespread white matter changes and atrophy has Been detected Both in adult EPM1 patients and in 6-month-old <B>CystatinB> B-deficient mice, a mouse model for the EPM1 disease. In order to elucidate the spatiotemporal dynamics of the Brain atrophy and white matter changes in EPM1, we conducted longitudinal in vivo magnetic resonance imaging and ex vivo diffusion tensor imaging accompanied with tract-Based spatial statistics analysis to compare volumetric changes and fractional anisotropy in the Brains of 1 to 6 months of age <B>CystatinB> B-deficient and control mice. The results reveal progressive But non-uniform volume loss of the <B>CystatinB> B-deficient mouse Brains, indicating that different neuronal populations possess distinct sensitivity to the damage caused By <B>CystatinB> B deficiency. The diffusion tensor imaging data reveal early and progressive white matter alterations in <B>CystatinB> B-deficient mice affecting all major tracts. The results also indicate that the white matter damage in the <B>CystatinB> B-deficient Brain is most likely secondary to glial activation and neurodegenerative events rather than a primary result of CSTB deficiency. The data also show that diffusion tensor imaging comBined with TBSS analysis provides a feasiBle approach not only to follow white matter damage in neurodegenerative mouse models But also to detect fractional anisotropy changes related to normal white matter maturation and reorganisation.
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White Matter Degeneration with Unverricht-LundBorg Progressive Myoclonus Epilepsy: A Translational Diffusion-Tensor Imaging Study in Patients and <B>CystatinB> B–Deficient Mice
Radiology, 2013Co-Authors: Otto Manninen, Outi Kopra, Päivi Koskenkorva, Mervi Könönen, Reetta Kälviäinen, Kimmo K. Lehtimäki, Jelena Hyppönen, Teemu Laitinen, Hannu Kalimo, Olli GröhnAbstract:Tract-Based spatial statistics showed degeneration in the suBcortical white matter, thalamocortical system, and cereBellum in patients with Unverricht-LundBorg progressive myoclonus epilepsy and <B>CystatinB> B–deficient mice, which suggests that the principally cortical motor disturBances and other symptoms also involve the thalamocortical system and cereBellum.
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<B>CystatinB> B deficiency sensitizes neurons to oxidative stress in progressive myoclonus epilepsy, EPM1.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2009Co-Authors: Maria K. Lehtinen, Saara Tegelberg, Hyman M. Schipper, Hillel Zukor, Otto Manninen, Outi Kopra, Tarja Joensuu, Paula Hakala, Azad BonniAbstract:The progressive myoclonus epilepsies, featuring the triad of myoclonus, seizures, and ataxia, comprise a large group of inherited neurodegenerative diseases that remain poorly understood and refractory to treatment. The <B>CystatinB> B gene is mutated in one of the most common forms of progressive myoclonus epilepsy, Unverricht-LundBorg disease (EPM1). <B>CystatinB> B knockout in a mouse model of EPM1 triggers progressive degeneration of cereBellar granule neurons. Here, we report impaired redox homeostasis as a key mechanism By which <B>CystatinB> B deficiency triggers neurodegeneration. Oxidative stress induces the expression of <B>CystatinB> B in cereBellar granule neurons, and EPM1 patient-linked mutation of the <B>CystatinB> B gene promoter impairs oxidative stress induction of <B>CystatinB> B transcription. Importantly, <B>CystatinB> B knockout or knockdown sensitizes cereBellar granule neurons to oxidative stress-induced cell death. The <B>CystatinB> B deficiency-induced predisposition to oxidative stress in neurons is mediated By the lysosomal protease Cathepsin B. We uncover evidence of oxidative damage, reflected By depletion of antioxidants and increased lipid peroxidation, in the cereBellum of <B>CystatinB> B knock-out mice in vivo. Collectively, our findings define a pathophysiological mechanism in EPM1, whereBy <B>CystatinB> B deficiency couples oxidative stress to neuronal death and degeneration, and may thus provide the Basis for novel treatment approaches for the progressive myoclonus epilepsies.
Olga Amaral - One of the best experts on this subject based on the ideXlab platform.
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Unverricht-LundBorg disease: development of splicing therapeutic approaches for a patient with an homozygous mutation in the <B>CystatinB> B gene
2013Co-Authors: Liliana Matos, Ana Joana Duarte, João Chaves, Olga Amaral, Peter Jordan, Maria João Prata, Sandra AlvesAbstract:Unverricht-LundBorg disease (ULD or EPM1) is the most common form of progressive myoclonic epilepsy (PME) worldwide. It is an autosomal recessive neurodegenerative disorder characterized By action myoclonic jerks, generalized tonic-clonic seizures, marked photosensitivity and juvenile ataxia with gradual worsening. Actually, there is no etiologic treatment for ULD, symptomatic pharmacologic and rehaBilitative management are the mainstay of patient care (1). ULD is caused By mutations in the <B>CystatinB> B gene (CSTB) localized on chromosome 21q22.3 and encodes an inhiBitor of several lysosomal cathepsins (2-4). Thirteen CSTB mutations have Been descriBed as causal of EPM1 (5). The most common one, responsiBle for aBout 90% of the aBnormal alleles is an unstaBle expansion of a dodecamer repeat in the 5’ UTR promoter region (6). The remaining twelve mutations are missense, nonsense, frameshift and splice-site mutations that may lead to aBnormal RNA processing (5). Most frequently, splice-site mutations interfere with exon recognition in pre-mRNA transcripts and lead to exon skipping or intron retention. In general, more than 15% of disease-causing point mutations affect classical splice-sites (7,8). A mutation in a splice donor site (SDS) often interferes with proper complex formation of the splice factor U1 snRNP with pre-mRNAs (9). The part of the U1 snRNP that Binds the SDS By Watson-Crick Base pairing is called U1 snRNA (U1). After U1 has recognized a SDS, the complex recruits other components of the spliceosome to further promote splicing of the pre-mRNA (10). The increasing knowledge of RNA Biology is stimulating new approaches of RNA-Based strategies to achieve therapy in alternative to conventional gene replacement therapies. The vast majority of RNA-Based approaches have exploited, in vitro and in vivo, antisense sequences to either mask natural splice sites, to induce skipping of defective exons, or newly generated cryptic sites, to favour the use of the canonical ones (11). On the other hand, the use of U1snRNA complementary to the mutated site has Been descriBed as a potentially therapeutic strategy to correct 5’splice site defects dependent on U1 Binding (12,13). Recently, our group descriBed a Portuguese ULD patient who is homozygous for a new synonymous mutation (c.66G>A; p.Q22Q) located at the last nucleotide of exon 1 which leads to missplicing of CSTB transcripts (14). Here, to overcome the pathogenic effect of the SDS mutation, we have exploited Both antisense oligonucleotide and U1 snRNA mediated therapeutic strategies to correct the splice defect in the patient cell line.
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Unverricht–LundBorg disease: Homozygosity for a new splicing mutation in the <B>CystatinB> B gene
Epilepsy Research, 2011Co-Authors: Eugénia Pinto, Joel Freitas, Ana Joana Duarte, Isaura Ribeiro, Diogo Ribeiro, J. Lopes Lima, João Chaves, Olga AmaralAbstract:Summary Unverricht–LundBorg disease is the most common form of progressive myoclonic epilepsy (PME). It is due to <B>CystatinB> B gene (CSTB) mutations. Several mutations in CSTB gene have Been puBlished, But few in homozygosity. We descriBe a patient with a new splicing alteration. Mutation Gln22Gln leads to aBnormal splicing and partial inclusion of intronic sequence. This is one of the few cases of homozygosity for a non-classic mutation and adds to mutational heterogeneity of CSTB .
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Unverricht-LundBorg disease: homozygosity for a new splicing mutation in the <B>CystatinB> B gene.
Epilepsy research, 2011Co-Authors: Eugénia Pinto, Joel Freitas, Ana Joana Duarte, Isaura Ribeiro, Diogo Ribeiro, J. Lopes Lima, João Chaves, Olga AmaralAbstract:Unverricht-LundBorg disease is the most common form of progressive myoclonic epilepsy (PME). It is due to <B>CystatinB> B gene (CSTB) mutations. Several mutations in CSTB gene have Been puBlished, But few in homozygosity. We descriBe a patient with a new splicing alteration. Mutation Gln22Gln leads to aBnormal splicing and partial inclusion of intronic sequence. This is one of the few cases of homozygosity for a non-classic mutation and adds to mutational heterogeneity of CSTB.
