SNCG gene silencing in gallbladder cancer cells inhibits key tumorigenic activities.
Source
Department of Hepatobiliary Surgery, Union Hospital, Fujian Medical University, Fuzhou 350001, China.
Abstract
We recently determined that synuclein-gamma (SNCG) is highly expressed in human gallbladder cancer (GBC), and its abnormal expression is associated with tumor aggressiveness. To investigate the effects of SNCG gene silencing on the tumorigenic profiles of the GBC cell line, NOZ, short-hairpin RNA (shRNA) interference was employed. Specifically, the SNCG transcript was targeted by SNCG-shRNA lentiviral particles designed to silence SNCG gene expression. Following selection of NOZ cells stably expressing SNCG-shRNA, SNCG expression was examined by western blot and semi-quantitative RT-PCR analyses. Phenotypic hallmarks of gallbladder carcinogenesis were assayed by CCK-8, soft agar (colony formation), modified Boyden-Chamber (invasion), and flow cytometry (cell-cycle and apoptosis) assays. Our results showed that SNCG gene silencing in NOZ cells inhibited cell growth, colony formation, and invasion. In addition, it directly increased the effectiveness of paclitaxel in inducing G2/M cell-cycle arrest and cell apoptosis. Data from our in vivo study showed a decrease in tumor growth and weight in mice injected with SNCG-silenced NOZ cells. Together, these findings suggest that SNCG plays an important role in the progression of GBC.
- PMID:
- 22201822
- [PubMed - in process]
Autosomal dominant Parkinson's disease.
Source
Department of Neurology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
Abstract
Over the past two decades the understanding and classification of Parkinson's disease (PD) has been revolutionized by genetic research. Currently, sixteen PARK loci have been identified with autosomal dominant genes such as SNCA, and LRRK2, and autosomal recessive genes such as PRKN, DJ-1, and PINK1. Among these genes, LRRK2 is the most prevalent. Additionally, susceptibility variants located on some of these genes are widely recognized as risk factors for PD in certain ethnic populations. Alpha synuclein Lewy body (LB) pathology, the hallmark of sporadic PD, is predominantly seen in carriers of SNCA and LRRK2. Recently two new autosomal dominant PD genes have been discovered, eukaryotic translation initiation factor 4-gamma (EIF4G1) and vacuolar protein sorting 35 (VPS35). EIF4G1 is associated with LB pathology; however, only limited data currently exists on pathology of the VPS35. Thus, it remains to be seen if LB pathology can be identified on autopsy examination of carriers of VPS35 gene. The mechanism behind the cause of PD has yet to be elucidated; however, genetic studies on autosomal dominant PD have provided novel insights into the potential etiology of PD. Thus, paving the way for future targeted therapies aimed at disease prevention and cure.
Copyright © 2011 Elsevier Ltd. All rights reserved.
Dimebon Slows Progression of Proteinopathy in γ-Synuclein Transgenic Mice.
Source
Institute of Physiologically Active Compounds of RAS, 1 Severniy Proezd, Chernogolovka, 142432, Moscow Region, Russian Federation.
Abstract
Intermediates and final products of protein aggregation play crucial role in the development of degenerative changes in a number of neurological diseases. Pathological protein aggregation is currently regarded as one of the most promising therapeutic targets for treatment of these diseases. Transgenic mouse models of proteinopathies are an effective tool for screening and validation of compounds, which can selectively affect metabolism of aggregate-prone proteins. In this study, we assessed effects of dimebon, a compound with known neuroprotective properties, on a recently established transgenic mouse model recapitulating key pathological features of amyotrophic lateral sclerosis (ALS) as the consequence of neuron-specific overexpression of γ-synuclein. Cohorts of experimental transgenic mice received dimebon in drinking water with this chronic treatment starting either before or after the onset of clinical signs of pathology. We detected statistically significant improvement of motor performance in a rotarod test in both dimebon-treated animal groups, with more pronounced effect in a group that received dimebon from an earlier age. We also revealed substantially reduced number of amyloid inclusions, decreased amount of insoluble γ-synuclein species and a notable amelioration of astrogliosis in the spinal cord of dimebon-treated compared with control transgenic animals. However, dimebon did not prevent the loss of spinal motor neurons in this model. Our results demonstrated that chronic dimebon administration is able to slow down but not halt progression of γ-synucleinopathy and resulting signs of pathology in transgenic animals, suggesting potential therapeutic use of this drug for treatment of this currently incurable disease.
α-Synuclein potentiates interleukin-1β-induced CXCL10 expression in human A172 astrocytoma cells.
Source
Department of Pharmacology/Physiology, Oklahoma State University Center for Health Sciences, Tulsa, OK 74107, United States.
Abstract
Neuroinflammation and neuronal degeneration observed in Parkinson's disease (PD) has been attributed in part to glial-mediated events. Increased expression of proinflammatory cytokines and abnormal accumulation of the neuronal protein, α-synuclein in the brain are also characteristic of PD. While increasing evidence suggests that astrocytes contribute to neuroinflammation and dopaminergic neuronal degeneration associated with PD, there remains much to learn about these astroglial-mediated events. Therefore, we investigated the in vitro effects of interleukin-1β (IL-1β) and α-synuclein on astroglial expression of interferon-γ inducible protein-10 (CXCL10), a proinflammatory and neurotoxic chemokine. IL-1β-induced CXCL10 protein expression was potentiated by co-exposure to α-synuclein. α-Synuclein did not significantly affect IL-1β-induced CXCL10 mRNA expression, but did mediate increased CXCL10 mRNA stability, which may explain, in part, the increased levels of secreted CXCL10 protein. Future investigations are warranted to more fully define the mechanism by which α-synuclein enhances IL-1β-induced astroglial CXCL10 expression. These findings highlight the importance of α-synuclein in modulating inflammatory events in astroglia. These events may be particularly relevant to the pathology of CNS disorders involving α-synuclein accumulation, including PD and HIV-1 associated dementia.
Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.
[Role of genetics in the etiology of synucleinopathies].
Source
Grupo de Investigación BIOMICS, Departamento de Biología Celular A, Centro de Investigación y Estudios Avanzados (CIEA) Lucio Lascaray, Universidad del País Vasco UPV/EHU, Vitoria-Gasteiz, España.
Abstract
The protein family known as synucleins is composed of α-, β- and γ-synuclein. The most widely studied is the α-synuclein protein due to its participation in essential processes of the central nervous system. Neurotoxicity of this protein is related to the presence of multiplications (duplications and triplications) and point mutations in the gene sequence of the α-synuclein gene (SNCA), differential expression of its isoforms and variations in post-transductional modifications. Neurotoxicity is also related to cytoplasmic inclusions known as Lewy bodies (LBs) and Lewy neurites (LNs), which are also present in α-synucleinopathies. In general, the β-synuclein protein, codified by the SNCB gene, acts as a regulator of processes triggered by α-synuclein and its function is altered by variations in the gene sequence, while γ-synuclein, codified by the SNCG gene, seems to play a major role in certain tumoral processes.
Copyright © 2011 SEGG. Published by Elsevier Espana. All rights reserved.
Deletion of alpha-synuclein decreases impulsivity in mice.
Source
School of Psychology, University of Sussex, Falmer, Brighton BN1 9QG, UK School of Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3AX, UK Behavioural and Clinical Neuroscience Institute and Department of Experimental Psychology, University of Cambridge, Downing Street, Cambridge CB2 3EB, UK Department of Psychiatry, Addenbrooke's Hospital, University of Cambridge, Hill's Road, Cambridge CB2 2QQ, UK Institute of Psychiatry, Kings College, Denmark Hill, London, SE5 8AF.
Abstract
The presynaptic protein alpha-synuclein, associated with Parkinson's Disease (PD), plays a role in dopaminergic neurotransmission and is implicated in impulse control disorders (ICDs) such as drug addiction. In this study we investigated a potential causal relationship between alpha-synuclein and impulsivity, by evaluating differences in motor impulsivity in the 5-choice serial reaction time task (5-CSRTT) in strains of mice that differ in the expression of the alpha-synuclein gene. C57BL/6JOlaHsd mice differ from their C57BL/6J ancestors in possessing a chromosomal deletion resulting in the loss of two genes, snca, encoding alpha-synuclein, and mmrn1, encoding multimerin-1. C57BL/6J mice displayed higher impulsivity (more premature responding) than C57BL/6JOlaHsd mice when the pre-stimulus waiting interval was increased in the 5-CSRTT. In order to ensure that the reduced impulsivity was indeed related to snca, and not adjacent gene deletion, wild type (WT) and mice with targeted deletion of alpha-synuclein (KO) were tested in the 5-CSRTT. Similarly, WT mice were more impulsive than mice with targeted deletion of alpha-synuclein. Interrogation of our ongoing analysis of impulsivity in BXD recombinant inbred mouse lines revealed an association of impulsive responding with levels of alpha-synuclein expression in hippocampus. Expression of beta- andgamma-synuclein, members of the synuclein family that may substitute for alpha-synuclein following its deletion, revealed no differential compensations among the mouse strains. These findings suggest that alpha-synuclein may contribute to impulsivity and potentially, to ICDs which arise in some PD patients treated with dopaminergic medication.
© 2011 The Authors. Genes, Brain and Behavior © 2011 Blackwell Publishing Ltd and International Behavioural and Neural Genetics Society.
Expression of ERα, its ERαΔ3 Splice Variant and γ-SYNUCLEIN in Ovarian Cancer: A Pilot Study.
Source
Centre for Biophotonics, Lancaster Environment Centre, Lancaster University, Lancaster LA1 4YQ, UK.
Abstract
AIMS:
Ovarian cancer has the highest mortality of any gynaecological malignancy; this is due to rapid peritoneal spread of tumour cells and neovascularization. Understanding the mechanisms underlying this is critical to developing early diagnostic or treatment strategies. We devised a pilot study to examine the role of γ-SYNUCLEIN (γ-SYN), oestrogen receptor (ER)α, and the splice variant ERαΔ3.
METHODOLOGY:
With ethical approval, ovarian tissue was collected from patients (n=24) undergoing oopherectomy for non-ovarian pathology or primary surgery for suspected ovarian cancer. Quantitative gene expression analysis was employed for γ-SYN, ERα, and ERαΔ3. To identify the in situ localization, immunofluorescence for γ-syn was carried out.
RESULTS:
Ovarian tumour tissue exhibited an elevated expression of γ-SYN and high-grade tumours had an elevated ERαΔ3:ERα ratio compared with benign tissue. The majority of previous studies point to the γ-syn protein being present in epithelial cells of high-grade disease. Our study supports this, but additionally we conclusively identify its presence in the endothelial cells of vasculature surrounding low-grade disease; immunofluorescence was strongest in the apical cells surrounding the lumen.
CONCLUSION:
Our results demonstrate for the first time that there are readily-expressed levels of γ-SYN and ERαΔ3 in normal ovarian tissue and ovarian tumours. In high-grade disease, γ-syn and an elevated ERαΔ3:ERα ratio might confer metastatic potential to the tumourigenic cells and promote neoangiogenesis. Future in vitro studies might be necessary to delineate such a mechanism, which could potentially be the basis of early intervention.
Synuclein-γ (SNCG) protein expression is associated with poor outcome in endometrial adenocarcinoma.
Source
Department of Pathology, Roswell Park Cancer Institute, Buffalo, NY, USA.
Abstract
OBJECTIVE:
Synuclein-γ (SNCG) is a marker for adverse and aggressive disease in breast cancer. In previous study, we found SNCG mRNA to be overexpressed in uterine serous carcinoma compared to uterine endometrioid adenocarcinoma. The aim of this study is to explore the prognostic value of SNCG in patients with endometrial cancer.
METHODS:
279 endometrial cancer patients were retrieved from the archives. The tissue paraffin blocks were stained for SNCG antibody and its expression was correlated with clinicopathological prognostic factors.
RESULTS:
There was a positive association between SNCG(+) immunoexpression and tumor grade, tumor stage, type II carcinomas, deep myometrial invasion and lymphovascular invasion. A correlation between SNCG(+) and adverse outcomes, such as shorter overall survival (OS) and disease free survival (DFS), was also detected. Following adjuvant therapy (radiation and chemotherapy or chemotherapy alone), we observed a difference in 5years DFS rate between SNCG(+) (41.6%) and SNCG(-) patients (59.5%).
CONCLUSION:
Overexpression of SNCG seemed to be a predictor biomarker for aggressive tumor behavior and adverse outcome in patients with endometrial cancer. Future exploration of SNCG as a potential therapeutic target for selected patients could be of interest.
Copyright © 2011 Elsevier Inc. All rights reserved.
Immunohistochemical localization of aggresomal proteins in glial cytoplasmic inclusions in multiple system atrophy.
Source
Department of Pathology, Institute for Developmental Research, Aichi Human Service Center, 713-8 Kamiya, Kasugai, Aichi 480-0392 Japan Department of Embryology, Institute for Developmental Research, Aichi Human Service Center, 713-8 Kamiya, Kasugai, Aichi 480-0392 Japan Department of Neuropathology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582 Japan.
Abstract
Aims: Multiple system atrophy (MSA) is pathologically characterized by the formation of α-synuclein-containing glial cytoplasmic inclusions (GCIs) in oligodendrocytes. However, the mechanisms of GCI formation are not fully understood. Cellular machinery for the formation of aggresomes has been linked to the biogenesis of the Lewy body, a characteristic α-synuclein-containing inclusion of Parkinson's disease and dementia with Lewy bodies. Here we examined whether GCIs contain the components of aggresomes by immunohistochemistry. Methods: Sections from 5 patients with MSA were stained immunohistochemically with antibodies against aggresome-related proteins and analyzed in comparison with sections from 5 patients with no neurological disease. We evaluated the presence or absence of aggresome-related proteins in GCIs by double immunofluorescence and immuno-electron microscopy. Results: GCIs were clearly immunolabeled with antibodies against aggresome-related proteins, such as γ-tubulin, histone deacetylase 6 (HDAC6), and 20S proteasome subunits. Neuronal cytoplasmic inclusions (NCIs) were also immunopositive for these aggresome-related proteins. Double immunofluorescence staining and quantitative analysis demonstrated that the majority of GCIs contained these proteins, as well as other aggresome-related proteins, such as Hsp70, Hsp90, and 62 kDa protein/sequestosome 1 (p62/SQSTM1). Immuno-electron microscopy demonstrated immunoreactivities for γ-tubulin and HDAC6 along the fibrils comprising GCIs. Conclusions: Our results indicate that GCIs, and probably NCIs, share at least some characteristics with aggresomes in terms of their protein components. Therefore, GCIs and NCIs may be another manifestation of aggresome-related inclusion bodies observed in neurodegenerative diseases.
© 2011 The Authors. Neuropathology and Applied Neurobiology © 2011 British Neuropathological Society.
A53T-alpha-synuclein-overexpression in the mouse nigrostriatal pathway leads to early increase of 14-3-3 epsilon and late increase of GFAP.
Source
Department of Neurology, Goethe University Medical School, 60590, Frankfurt, Germany.
Abstract
Parkinson's disease (PD) is a neurodegenerative disorder frequent at old age characterized by atrophy of the nigrostriatal projection. Overexpression and A53T-mutation of the presynaptic, vesicle-associated chaperone alpha-synuclein are known to cause early-onset autosomal dominant PD. We previously generated mice with transgenic overexpression of human A53T-alpha-synuclein (A53T-SNCA) in dopaminergic substantia nigra neurons as a model of early PD. To elucidate the early and late effects of A53T-alpha-synuclein on the proteome of dopaminergic nerve terminals in the striatum, we now investigated expression profiles of young and old mice using two-dimensional fluorescence difference in gel electrophoresis (2D-DIGE) and mass spectrometry. In total, 15 proteins were upregulated and 2 downregulated. Mice before the onset of motor anomalies showed an upregulation of the spot containing 14-3-3 proteins, in particular the epsilon isoform, as well as altered levels of chaperones, vesicle trafficking and bioenergetics proteins. In old mice, the persistent upregulation of 14-3-3 proteins was aggravated by an increase of glial fibrillary acidic protein (GFAP) suggesting astrogliosis due to initial neurodegeneration. Independent immunoblots corroborated GFAP upregulation and 14-3-3 upregulation for the epsilon isoform, and also detected significant eta and gamma changes. Only for 14-3-3 epsilon a corresponding mRNA increase was observed in midbrain, suggesting it is transcribed in dopaminergic perikarya and accumulates as protein in presynapses, together with A53T-SNCA. 14-3-3 proteins associate with alpha-synuclein in vitro and in pathognomonic Lewy bodies of PD brains. They act as chaperones in signaling, dopamine synthesis and stress response. Thus, their early dysregulation probably reflects a response to alpha-synuclein toxicity.
γ-Synuclein is a promising new marker for staining reactive follicular dendritic cells, follicular dendritic cell sarcoma, Kaposi sarcoma, and benign and malignant vascular tumors.
Source
Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York 10467-2490, USA.
Abstract
Synucleins are small soluble proteins found in normal brain that facilitate rapid release of neurotransmitters. α-synucleinis a major component of the Lewy body of neurodegenerative diseases and γ-synuclein is a marker of aggressive carcinomas. As the role of γ-synuclein has not yet been investigated in the lymphoid system, we immunohistochemically stained normal lymphoid organs, lymph nodes with reactive lymphoid hyperplasia, and malignant lymphomas. The anti-γ-synuclein antibody strongly stained the follicular dendritic cell (FDC) meshworks and vascular and lymphatic endothelial cells in reactive lymphoid tissues, in B-cell lymphomas with a nodular pattern, and in angioimmunoblastic T-cell lymphomas. There were no γ-synuclein-positive FDC meshworks in B-cell or T-cell lymphomas with a diffuse pattern. This is in contrast to CD21, which only stained the arms of the FDCs; γ-synucleinhighlighted both the long slender cellular processes and the cell body, thereby clearly demonstrating the number of individual FDCs. In addition, γ-synuclein was strongly expressed by the neoplastic counterpart of reactive FDCs (FDC sarcoma) and by the neoplastic counterparts of normal lymphatic and vascular endothelial cells (Kaposi sarcoma, hemangioma, and angiosarcoma). Only a few spindle cell neoplasms (SSNs) derived from smooth muscle, peripheral nerve, or gastrointestinal stroma expressed γ-synuclein; however, γ-synuclein was not expressed by 11 other types of SSNs tested. These results suggest that γ-synuclein is a promising new adjunct marker for identifying reactive FDCs and for diagnosing FDC sarcoma and benign and malignant vascular tumors.
SNCG shRNA suppressed breast cancer cell xenograft formation and growth in nude mice.
Source
Department of Oncology, the First Affiliated Hospital, Zhengzhou University, Zhengzhou, Henan 450051, China.
Abstract
BACKGROUND:
Overexpression of breast cancer-specific gene 1 (SNCG) is associated with poor prognosis in advanced breast cancer patients. This study aimed to determine the effects of SNCG knockdown in breast cancer cells by using small hairpin RNA (shRNA).
METHODS:
Four different SNCG shRNA oligonucleotides were designed and chemically synthesized to construct mammalian expression vectors. These vectors were then stably transfected into a breast cancer MCF-7 cell line to knockdown SNCG expression. After SNCG knockdown was confirmed, the stable cell lines were inoculated into nude mice. SNCG mRNA and protein expressions were analyzed by semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry, respectively in both the stable cell lines and xenografts.
RESULTS:
All four SNCG shRNA constructs significantly reduced SNCG mRNA and protein levels in MCF-7 cells, as compared to the unrelated sequence control shRNA and the liposome control mice (P < 0.05). SNCG-knockdown MCF-7 cells formed significantly smaller tumor masses than cells expressing the unrelated sequence control or the liposome control mice (P < 0.05).
CONCLUSION:
SNCG shRNA effectively suppressed breast cancer cell formation in vivo and may be a useful clinical strategy to control breast cancer.
Functional alterations to the nigrostriatal system in mice lacking all three members of the synuclein family.
Source
Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, United Kingdom.
Abstract
The synucleins (α, β, and γ) are highly homologous proteins thought to play a role in regulating neurotransmission and are found abundantly in presynaptic terminals. To overcome functional overlap between synuclein proteins and to understand their role in presynaptic signaling from mesostriatal dopaminergic neurons, we produced mice lacking all three members of the synuclein family. The effect on the mesostriatal system was assessed in adult (4- to 14-month-old) animals using a combination of behavioral, biochemical, histological, and electrochemical techniques. Adult triple-synuclein-null (TKO) mice displayed no overt phenotype and no change in the number of midbrain dopaminergic neurons. TKO mice were hyperactive in novel environments and exhibited elevated evoked release of dopamine in the striatum detected with fast-scan cyclic voltammetry. Elevated dopamine release was specific to the dorsal not ventral striatum and was accompanied by a decrease of dopamine tissue content. We confirmed a normal synaptic ultrastructure and a normal abundance of SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) protein complexes in the dorsal striatum. Treatment of TKO animals with drugs affecting dopamine metabolism revealed normal rate of synthesis, enhanced turnover, and reduced presynaptic striatal dopamine stores. Our data uniquely reveal the importance of the synuclein proteins in regulating neurotransmitter release from specific populations of midbrain dopamine neurons through mechanisms that differ from those reported in other neurons. The finding that the complete loss of synucleins leads to changes in dopamine handling by presynaptic terminals specifically in those regions preferentially vulnerable in Parkinson's disease may ultimately inform on the selectivity of the disease process.
Direct membrane association drives mitochondrial fission by the Parkinson disease-associated protein alpha-synuclein.
Source
Department of Neurology and Physiology, University of California, San Francisco, California 94158, USA.
Abstract
The protein α-synuclein has a central role in Parkinson disease, but the mechanism by which it contributes to neural degeneration remains unknown. We now show that the expression of α-synuclein in mammalian cells, including neurons in vitro and in vivo, causes the fragmentation of mitochondria. The effect is specific for synuclein, with more fragmentation by α- than β- or γ-isoforms, and it is not accompanied by changes in the morphology of other organelles or in mitochondrial membrane potential. However, mitochondrial fragmentation is eventually followed by a decline in respiration and neuronal death. The fragmentation does not require the mitochondrial fission protein Drp1 and involves a direct interaction of synuclein with mitochondrial membranes. In vitro, synuclein fragments artificial membranes containing the mitochondrial lipid cardiolipin, and this effect is specific for the small oligomeric forms of synuclein. α-Synuclein thus exerts a primary and direct effect on the morphology of an organelle long implicated in the pathogenesis of Parkinson disease.
- PMID:
- 21489994
- [PubMed - indexed for MEDLINE]
- PMCID: PMC3121472
- [Available on 2012/6/10]
[Targeted inactivation of gamma-synuclein gene affects anxiety and exploratory behaviour of mice].
Abstract
Gamma(gamma)-synuclein is a member of synuclein family of cytoplasmic and predominantly neuronal proteins found only in vertebrates. Gamma-synuclein is abundant in axons and presynaptic terminals of neurons localized in brain regions involved in emotions, learning and memory. However, the role of gamma-synuclein in these brain functions was not previously assessed. We have demonstrated for the first time that the loss of gamma-synuclein results in a significant increase in the level of orientation response in novel environment and decrease in the level of state anxiety.
- PMID:
- 21469331
- [PubMed - indexed for MEDLINE]
Synuclein modulation of monoamine transporters.
Source
Department of Biochemistry, Molecular, Cellular Biology and Lombardi Cancer Center, Georgetown University, Washington, DC 20007, United States.
Abstract
Although well-studied in the context of neurodegenerative disease, a clear biological function for the synuclein proteins remains elusive. Emerging data indicate a role for synucleins in monoamine neurotransmitter homeostasis. A key regulatory component of monoamine neurotransmission is re-uptake of neurotransmitter by the dopamine transporter, norepinephrine transporter, and serotonin transporter, which are common drug targets in the treatment of depression and other mood disorders. Through interactions with these transporters, the neuronal cytoskeleton, and pre-synaptic scaffolding proteins, α-synuclein, β-synuclein, and γ-synuclein modulate trafficking, expression and function of monoamine transporters at the cell surface, thus playing a central role in regulating monoamine re-uptake.
Copyright © 2011 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
- PMID:
- 21396366
- [PubMed - indexed for MEDLINE]
- PMCID: PMC3071522
- [Available on 2012/4/6]
Alpha- and beta-synucleins are new diagnostic tools for acute erythroid leukemia and acute megakaryoblastic leukemia.
Source
Montefiore Medical Center /Albert Einstein College of Medicine Bronx, Bronx, New York 10467, USA.
Abstract
α-Synuclein is a key component of the Lewy body, a large globular protein complex that forms in the nervous system of patients with Parkinson disease and other dementias [1-3]. Since α-synuclein also occurs in megakaryocytic and erythroid lineages [4-7], we wondered what role synucleins had in the hematopoietic system. Therefore, we studied the expression of α-, β-, and γ-synucleins in a comprehensive panel of patient bone marrows and leukemic cell lines. We observed under expression of α-synuclein in the megakaryocytes of myeloproliferative neoplasm (MPN), but not normal reactive marrow (NRM) or myelodysplastic syndrome (MDS). Conversely, we observed over expression of β-synuclein in the blasts of megakaryoblastic leukemias (MegL), but not acute myeloid leukemia (AML) or erythroleukemia (EryL), suggesting that α- and β-synucleins could be useful adjunct markers for the early detection of MDS and the differential diagnosis of EryL and MegL from other AMLs.
Myelination transition zone astrocytes are constitutively phagocytic and havesynuclein dependent reactivity in glaucoma.
Source
The Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Abstract
Optic nerve head (ONH) astrocytes have been proposed to play both protective and deleterious roles in glaucoma. We now show that, within the postlaminar ONH myelination transition zone (MTZ), there are astrocytes that normally express Mac-2 (also known as Lgals3 or galectin-3), a gene typically expressed only in phagocytic cells. Surprisingly, even in healthy mice, MTZ and other ONH astrocytes constitutive internalize large axonal evulsions that contain whole organelles. In mouse glaucoma models, MTZ astrocytes further up-regulate Mac-2 expression. During glaucomatous degeneration, there are dystrophic processes in the retina and optic nerve, including the MTZ, which contain protease resistant γ-synuclein. The increased Mac-2 expression by MTZ astrocytes during glaucoma likely depends on this γ-synuclein, as mice lacking γ-synuclein fail to up-regulate Mac-2 at the MTZ after elevation of intraocular pressure. These results suggest the possibility that a newly discovered normal degradative pathway for axons might contribute to glaucomatous neurodegeneration.
[Expression of BCSG1-siRNA in tumor transplants of human breast cancer cell line in nude mice].
Source
Department of Pathology, the Fifth Affiliated Hospital, Zhengzhou University, Zhengzhou 450052, China. shpeihong2008@163.com
Abstract
OBJECTIVE:
To investigate the inhibitory effects of siRNA targeting BCSG1 gene expression in tumor transplants of human breast cancer cell line in nude mice.
METHODS:
Four-pairs of small interfering RNA sequences of BCSG1 were chemically synthesized and inserted into the plasmid expression vectors, and were then transfected into human breast carcinoma cell line MCF7 by liposome method. Plasmid vector with unrelated sequence was used as the vector control. Cells transfected with 4 siRNA sequences, control vector and naive FCF7 cells were transplanted into the nude mice. The tumor inhibition was analysised. Immunohistochemical SP method and semi-quantitative RT-PCR were adopted to detect the BCSG1 mRNA and protein expression, respectively. Breast tissue samples of human infiltrating ductal carcinoma, ductal hyperplasia and fibroadenoma were also used as the controls.
RESULTS:
The inhibition rates of tumor growth in four BCSG1-siRNA transfected groups were remarkably higher than those of the vector control group and naive MCF7 cells (P<0.01). Compared with that of the vector control and naïve MCF7 cell group, there was a significant decrease of BCSG-1 protein expression in the four experimental groups by immuno-histochemistry staining (P<0.01). In addition, BCSG1 mRNA expression in the four groups transfected with BCSG1-siRNA were significantly less than that of the control vector group, naive MCF7 cell control group and human breast IDC (P<0.01).
CONCLUSION:
BCSG1-siRNA down-regulates the expression of BCSG1 and inhibits effectively growth of the transplaned human breast cancer cell line in nude mice.
- PMID:
- 21176537
- [PubMed - indexed for MEDLINE]
Differential neuroprotective effects of 14-3-3 proteins in models of Parkinson's disease.
Source
Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, University of Alabama at Birmingham, Birmingham, AL 35294, USA. tyacoub@uab.edu
Abstract
14-3-3 proteins are important negative regulators of cell death pathways. Recent studies have revealed alterations in 14-3-3s in Parkinson's disease (PD) and the ability of 14-3-3s to interact with alpha-synuclein (α-syn), a protein central to PD pathophysiology. In a transgenic α-syn mouse model, we found reduced expression of 14-3-3θ, ε, and γ. These same isoforms prevent α-syn inclusion formation in an H4 neuroglioma cell model. Using dopaminergic cell lines stably overexpressing each 14-3-3 isoform, we found that overexpression of 14-3-3θ, ε, or γ led to resistance to both rotenone and 1-methyl-4-phenylpyridinium (MPP(+)), while other isoforms were not protective against both toxins. Inhibition of a single protective isoform, 14-3-3θ, by shRNA did not increase vulnerability to neurotoxic injury, but toxicity was enhanced by broad-based inhibition of 14-3-3 action with the peptide inhibitor difopein. Using a transgenic C. elegans model of PD, we confirmed the ability of both human 14-3-3θ and a C. elegans 14-3-3 homolog (ftt-2) to protect dopaminergic neurons from α-syn toxicity. Collectively, these data show a strong neuroprotective effect of enhanced 14-3-3 expression - particularly of the 14-3-3θ, ε, and γ isoforms - in multiple cellular and animal models of PD, and point to the potential value of these proteins in the development of neuroprotective therapies for human PD.
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