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Aubrey LD, Ninkina N, Ulamec SM, Abramycheva NY, Vasili E, Devine OM, Wilkinson M, Mackinnon E, Limorenko G, Walko M, Muwanga S, Amadio L, Peters OM, Illarioshkin SN, Outeiro TF, Ranson NA, Brockwell DJ, Buchman VL, Radford SE. Substitution of Met-38 to Ile in γ-synuclein found in two patients with amyotrophic lateral sclerosis induces aggregation into amyloid. Proc Natl Acad Sci U S A 2024; 121:e2309700120. [PMID: 38170745 PMCID: PMC10786281 DOI: 10.1073/pnas.2309700120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Accepted: 11/17/2023] [Indexed: 01/05/2024] Open
Abstract
α-, β-, and γ-Synuclein are intrinsically disordered proteins implicated in physiological processes in the nervous system of vertebrates. α-synuclein (αSyn) is the amyloidogenic protein associated with Parkinson's disease and certain other neurodegenerative disorders. Intensive research has focused on the mechanisms that cause αSyn to form amyloid structures, identifying its NAC region as being necessary and sufficient for amyloid assembly. Recent work has shown that a 7-residue sequence (P1) is necessary for αSyn amyloid formation. Although γ-synuclein (γSyn) is 55% identical in sequence to αSyn and its pathological deposits are also observed in association with neurodegenerative conditions, γSyn is resilient to amyloid formation in vitro. Here, we report a rare single nucleotide polymorphism (SNP) in the SNCG gene encoding γSyn, found in two patients with amyotrophic lateral sclerosis (ALS). The SNP results in the substitution of Met38 with Ile in the P1 region of the protein. These individuals also had a second, common and nonpathological, SNP in SNCG resulting in the substitution of Glu110 with Val. In vitro studies demonstrate that the Ile38 variant accelerates amyloid fibril assembly. Contrastingly, Val110 retards fibril assembly and mitigates the effect of Ile38. Substitution of residue 38 with Leu had little effect, while Val retards, and Ala increases the rate of amyloid formation. Ile38 γSyn also results in the formation of γSyn-containing inclusions in cells. The results show how a single point substitution can enhance amyloid formation of γSyn and highlight the P1 region in driving amyloid formation in another synuclein family member.
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Affiliation(s)
- Liam D. Aubrey
- Astbury Centre for Structural Molecular Biology, School of Molecular and Cellular Biology, Faculty of Biological Science, University of Leeds, LeedsLS2 9JT, United Kingdom
| | - Natalia Ninkina
- School of Biosciences, Cardiff University, CardiffCF10 3AX, United Kingdom
- Department of Pharmacology and Clinical Pharmacology, Belgorod State National Research University, Belgorod308015, Russian Federation
| | - Sabine M. Ulamec
- Astbury Centre for Structural Molecular Biology, School of Molecular and Cellular Biology, Faculty of Biological Science, University of Leeds, LeedsLS2 9JT, United Kingdom
| | - Natalia Y. Abramycheva
- Laboratory of Neurobiology and Tissue Engineering, Brain Science Institute, Research Center of Neurology, Moscow125367, Russia
| | - Eftychia Vasili
- Laboratory of Molecular and Chemical Biology of Neurodegeneration, Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, LausanneCH-1015, Switzerland
| | - Oliver M. Devine
- Astbury Centre for Structural Molecular Biology, School of Molecular and Cellular Biology, Faculty of Biological Science, University of Leeds, LeedsLS2 9JT, United Kingdom
| | - Martin Wilkinson
- Astbury Centre for Structural Molecular Biology, School of Molecular and Cellular Biology, Faculty of Biological Science, University of Leeds, LeedsLS2 9JT, United Kingdom
| | - Eilish Mackinnon
- School of Biosciences, Cardiff University, CardiffCF10 3AX, United Kingdom
| | - Galina Limorenko
- School of Biosciences, Cardiff University, CardiffCF10 3AX, United Kingdom
- Laboratory of Molecular and Chemical Biology of Neurodegeneration, Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, LausanneCH-1015, Switzerland
| | - Martin Walko
- Astbury Centre for Structural Molecular Biology, School of Molecular and Cellular Biology, Faculty of Biological Science, University of Leeds, LeedsLS2 9JT, United Kingdom
- Astbury Centre for Structural Molecular Biology, School of Chemistry, University of Leeds, LeedsLS2 9JT, United Kingdom
| | - Sarah Muwanga
- School of Biosciences, Cardiff University, CardiffCF10 3AX, United Kingdom
| | - Leonardo Amadio
- School of Biosciences, Cardiff University, CardiffCF10 3AX, United Kingdom
| | - Owen M. Peters
- School of Biosciences, Cardiff University, CardiffCF10 3AX, United Kingdom
| | - Sergey N. Illarioshkin
- Laboratory of Neurobiology and Tissue Engineering, Brain Science Institute, Research Center of Neurology, Moscow125367, Russia
| | - Tiago F. Outeiro
- Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Göttingen, Göttingen37075, Germany
- Max Planck Institute for Multidisciplinary Sciences, Goettingen37075, Germany
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle Upon TyneNE2 4HH, United Kingdom
- Scientific employee with a honorary contract at Deutsches Zentrum für Neurodegenerative Erkrankungen, Göttingen37075, Germany
| | - Neil A. Ranson
- Astbury Centre for Structural Molecular Biology, School of Molecular and Cellular Biology, Faculty of Biological Science, University of Leeds, LeedsLS2 9JT, United Kingdom
| | - David J. Brockwell
- Astbury Centre for Structural Molecular Biology, School of Molecular and Cellular Biology, Faculty of Biological Science, University of Leeds, LeedsLS2 9JT, United Kingdom
| | - Vladimir L. Buchman
- School of Biosciences, Cardiff University, CardiffCF10 3AX, United Kingdom
- Department of Pharmacology and Clinical Pharmacology, Belgorod State National Research University, Belgorod308015, Russian Federation
| | - Sheena E. Radford
- Astbury Centre for Structural Molecular Biology, School of Molecular and Cellular Biology, Faculty of Biological Science, University of Leeds, LeedsLS2 9JT, United Kingdom
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Zanotti LC, Malizia F, Cesatti Laluce N, Avila A, Mamberto M, Anselmino LE, Menacho-Márquez M. Synuclein Proteins in Cancer Development and Progression. Biomolecules 2023; 13:980. [PMID: 37371560 PMCID: PMC10296229 DOI: 10.3390/biom13060980] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2023] [Revised: 05/19/2023] [Accepted: 05/22/2023] [Indexed: 06/29/2023] Open
Abstract
Synucleins are a family of small, soluble proteins mainly expressed in neural tissue and in certain tumors. Since their discovery, tens of thousands of scientific reports have been published about this family of proteins as they are associated with severe human diseases. Although the physiological function of these proteins is still elusive, their relationship with neurodegeneration and cancer has been clearly described over the years. In this review, we summarize data connecting synucleins and cancer, going from the structural description of these molecules to their involvement in tumor-related processes, and discuss the putative use of these proteins as cancer molecular biomarkers.
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Affiliation(s)
- Lucía C. Zanotti
- Instituto de Inmunología Clínica y Experimental de Rosario (IDICER, CONICET-UNR), Facultad de Ciencias Médicas (UNR), Rosario 3100, Argentina
- Instituto de Inmunología Clínica y Experimental, CONICET, Rosario 3100, Argentina
- Centro de Investigación y Producción de Reactivos Biológicos (CIPReB), Facultad de Ciencias Médicas (UNR), Suipacha 660, Rosario 2000, Argentina
- Centro de Investigación del Cáncer de Rosario, Red de Investigación del Cáncer de Rosario (RICaR), 37007 Salamanca, Spain
| | - Florencia Malizia
- Instituto de Inmunología Clínica y Experimental de Rosario (IDICER, CONICET-UNR), Facultad de Ciencias Médicas (UNR), Rosario 3100, Argentina
- Instituto de Inmunología Clínica y Experimental, CONICET, Rosario 3100, Argentina
- Centro de Investigación y Producción de Reactivos Biológicos (CIPReB), Facultad de Ciencias Médicas (UNR), Suipacha 660, Rosario 2000, Argentina
- Centro de Investigación del Cáncer de Rosario, Red de Investigación del Cáncer de Rosario (RICaR), 37007 Salamanca, Spain
| | - Nahuel Cesatti Laluce
- Instituto de Inmunología Clínica y Experimental de Rosario (IDICER, CONICET-UNR), Facultad de Ciencias Médicas (UNR), Rosario 3100, Argentina
- Instituto de Inmunología Clínica y Experimental, CONICET, Rosario 3100, Argentina
- Centro de Investigación y Producción de Reactivos Biológicos (CIPReB), Facultad de Ciencias Médicas (UNR), Suipacha 660, Rosario 2000, Argentina
- Centro de Investigación del Cáncer de Rosario, Red de Investigación del Cáncer de Rosario (RICaR), 37007 Salamanca, Spain
| | - Aylén Avila
- Centro de Investigación y Producción de Reactivos Biológicos (CIPReB), Facultad de Ciencias Médicas (UNR), Suipacha 660, Rosario 2000, Argentina
- Centro de Investigación del Cáncer de Rosario, Red de Investigación del Cáncer de Rosario (RICaR), 37007 Salamanca, Spain
| | - Macarena Mamberto
- Instituto de Inmunología Clínica y Experimental de Rosario (IDICER, CONICET-UNR), Facultad de Ciencias Médicas (UNR), Rosario 3100, Argentina
- Instituto de Inmunología Clínica y Experimental, CONICET, Rosario 3100, Argentina
- Centro de Investigación y Producción de Reactivos Biológicos (CIPReB), Facultad de Ciencias Médicas (UNR), Suipacha 660, Rosario 2000, Argentina
- Centro de Investigación del Cáncer de Rosario, Red de Investigación del Cáncer de Rosario (RICaR), 37007 Salamanca, Spain
| | - Luciano E. Anselmino
- Instituto de Inmunología Clínica y Experimental de Rosario (IDICER, CONICET-UNR), Facultad de Ciencias Médicas (UNR), Rosario 3100, Argentina
- Instituto de Inmunología Clínica y Experimental, CONICET, Rosario 3100, Argentina
- Centro de Investigación y Producción de Reactivos Biológicos (CIPReB), Facultad de Ciencias Médicas (UNR), Suipacha 660, Rosario 2000, Argentina
- Centro de Investigación del Cáncer de Rosario, Red de Investigación del Cáncer de Rosario (RICaR), 37007 Salamanca, Spain
| | - Mauricio Menacho-Márquez
- Instituto de Inmunología Clínica y Experimental de Rosario (IDICER, CONICET-UNR), Facultad de Ciencias Médicas (UNR), Rosario 3100, Argentina
- Instituto de Inmunología Clínica y Experimental, CONICET, Rosario 3100, Argentina
- Centro de Investigación y Producción de Reactivos Biológicos (CIPReB), Facultad de Ciencias Médicas (UNR), Suipacha 660, Rosario 2000, Argentina
- Centro de Investigación del Cáncer de Rosario, Red de Investigación del Cáncer de Rosario (RICaR), 37007 Salamanca, Spain
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Sharma M, Burré J. α-Synuclein in synaptic function and dysfunction. Trends Neurosci 2023; 46:153-166. [PMID: 36567199 PMCID: PMC9877183 DOI: 10.1016/j.tins.2022.11.007] [Citation(s) in RCA: 93] [Impact Index Per Article: 46.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 11/07/2022] [Accepted: 11/29/2022] [Indexed: 12/24/2022]
Abstract
α-Synuclein is a neuronal protein that is enriched in presynaptic terminals. Under physiological conditions, it binds to synaptic vesicle membranes and functions in neurotransmitter release, although the molecular details remain unclear, and it is controversial whether α-synuclein inhibits or facilitates neurotransmitter release. Pathologically, in synucleinopathies including Parkinson's disease (PD), α-synuclein forms aggregates that recruit monomeric α-synuclein and spread throughout the brain, which triggers neuronal dysfunction at molecular, cellular, and organ levels. Here, we present an overview of the effects of α-synuclein on SNARE-complex assembly, neurotransmitter release, and synaptic vesicle pool homeostasis, and discuss how the observed divergent effects of α-synuclein on neurotransmitter release can be reconciled. We also discuss how gain-of-function versus loss-of-function of α-synuclein may contribute to pathogenesis in synucleinopathies.
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Affiliation(s)
- Manu Sharma
- Appel Alzheimer's Disease Research Institute, Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA.
| | - Jacqueline Burré
- Appel Alzheimer's Disease Research Institute, Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA.
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Carnazza KE, Komer LE, Xie YX, Pineda A, Briano JA, Gao V, Na Y, Ramlall T, Buchman VL, Eliezer D, Sharma M, Burré J. Synaptic vesicle binding of α-synuclein is modulated by β- and γ-synucleins. Cell Rep 2022; 39:110675. [PMID: 35417693 PMCID: PMC9116446 DOI: 10.1016/j.celrep.2022.110675] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2021] [Revised: 01/23/2022] [Accepted: 03/22/2022] [Indexed: 12/16/2022] Open
Abstract
α-synuclein, β-synuclein, and γ-synuclein are abundantly expressed proteins in the vertebrate nervous system. α-synuclein functions in neurotransmitter release by binding to and clustering synaptic vesicles and chaperoning SNARE-complex assembly. Pathologically, aggregates originating from soluble pools of α-synuclein are deposited into Lewy bodies in Parkinson's disease and related synucleinopathies. The functions of β-synuclein and γ-synuclein in presynaptic terminals remain poorly studied. Using in vitro liposome binding studies, circular dichroism spectroscopy, immunoprecipitation, and fluorescence resonance energy transfer (FRET) experiments on isolated synaptic vesicles in combination with subcellular fractionation of brains from synuclein mouse models, we show that β-synuclein and γ-synuclein have a reduced affinity toward synaptic vesicles compared with α-synuclein, and that heteromerization of β-synuclein or γ-synuclein with α-synuclein results in reduced synaptic vesicle binding of α-synuclein in a concentration-dependent manner. Our data suggest that β-synuclein and γ-synuclein are modulators of synaptic vesicle binding of α-synuclein and thereby reduce α-synuclein's physiological activity at the neuronal synapse.
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Affiliation(s)
- Kathryn E Carnazza
- Helen and Robert Appel Alzheimer's Disease Research Institute, Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10021, USA
| | - Lauren E Komer
- Helen and Robert Appel Alzheimer's Disease Research Institute, Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10021, USA
| | - Ying Xue Xie
- Helen and Robert Appel Alzheimer's Disease Research Institute, Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10021, USA
| | - André Pineda
- Helen and Robert Appel Alzheimer's Disease Research Institute, Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10021, USA
| | - Juan Antonio Briano
- Helen and Robert Appel Alzheimer's Disease Research Institute, Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10021, USA
| | - Virginia Gao
- Helen and Robert Appel Alzheimer's Disease Research Institute, Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10021, USA
| | - Yoonmi Na
- Helen and Robert Appel Alzheimer's Disease Research Institute, Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10021, USA
| | - Trudy Ramlall
- Department of Biochemistry, Weill Cornell Medicine, New York, NY 10021, USA
| | - Vladimir L Buchman
- School of Biosciences, Cardiff University, Cardiff CF103AX, UK; Belgorod State National Research University, 85 Pobedy Street, Belgorod, Belgorod 308015, Russian Federation
| | - David Eliezer
- Department of Biochemistry, Weill Cornell Medicine, New York, NY 10021, USA
| | - Manu Sharma
- Helen and Robert Appel Alzheimer's Disease Research Institute, Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10021, USA
| | - Jacqueline Burré
- Helen and Robert Appel Alzheimer's Disease Research Institute, Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10021, USA.
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Zheng W, Wu F, Fu K, Sun G, Sun G, Li X, Jiang W, Cao H, Wang H, Tang W. Emerging Mechanisms and Treatment Progress on Liver Metastasis of Colorectal Cancer. Onco Targets Ther 2021; 14:3013-3036. [PMID: 33986602 PMCID: PMC8110277 DOI: 10.2147/ott.s301371] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Accepted: 03/24/2021] [Indexed: 12/24/2022] Open
Abstract
Colorectal cancer is currently the third largest malignant tumor in the world, with high new cases and high mortality. Metastasis is one of the most common causes of death of colorectal cancer, of which liver metastasis is the most fatal. Since the beginning of the Human Genome Project in 2001, people have gradually recognized the 3 billion base pairs that make up the human genome, of which only about 1.5% of the nucleic acid sequences are used for protein coding, including proto-oncogenes and tumor suppressor genes. A large number of differences in the expression of proto-oncogenes and tumor suppressor genes have also been found in the study of colorectal cancer, which proves that they are also actively involved in the progression of colorectal cancer and promote the occurrence of liver metastasis. Except for 1.5% of the coding sequence, the rest of the nucleic acid sequence does not encode any protein, which is called non-coding RNA. With the deepening of research, genome sequences without protein coding potential that were originally considered “junk sequences” may have important biological functions. Many years of studies have found that a large number of abnormal expression of ncRNA in colorectal cancer liver metastasis, indicating that ncRNA plays an important role in it. To explore the role and mechanism of these coding sequences and non-coding RNA in liver metastasis of colorectal cancer is very important for the early diagnosis and treatment of liver metastasis of colorectal cancer. This article reviews the coding genes and ncRNA that have been found in the study of liver metastasis of colorectal cancer in recent years, as well as the mechanisms that have been identified or are still under study, as well as the clinical treatment of liver metastasis of colorectal cancer.
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Affiliation(s)
- Wubin Zheng
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, People's Republic of China
| | - Fan Wu
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, People's Republic of China
| | - Kai Fu
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, People's Republic of China
| | - Guangshun Sun
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, People's Republic of China
| | - Guoqiang Sun
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, People's Republic of China
| | - Xiao Li
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, People's Republic of China
| | - Wei Jiang
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, People's Republic of China
| | - Hongyong Cao
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, People's Republic of China
| | - Hanjin Wang
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, People's Republic of China
| | - Weiwei Tang
- Hepatobiliary/Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Living Donor Transplantation, Chinese Academy of Medical Sciences, Nanjing, People's Republic of China
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The Role of Alpha-Synuclein and Other Parkinson's Genes in Neurodevelopmental and Neurodegenerative Disorders. Int J Mol Sci 2020; 21:ijms21165724. [PMID: 32785033 PMCID: PMC7460874 DOI: 10.3390/ijms21165724] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Revised: 07/29/2020] [Accepted: 08/08/2020] [Indexed: 12/13/2022] Open
Abstract
Neurodevelopmental and late-onset neurodegenerative disorders present as separate entities that are clinically and neuropathologically quite distinct. However, recent evidence has highlighted surprising commonalities and converging features at the clinical, genomic, and molecular level between these two disease spectra. This is particularly striking in the context of autism spectrum disorder (ASD) and Parkinson's disease (PD). Genetic causes and risk factors play a central role in disease pathophysiology and enable the identification of overlapping mechanisms and pathways. Here, we focus on clinico-genetic studies of causal variants and overlapping clinical and cellular features of ASD and PD. Several genes and genomic regions were selected for our review, including SNCA (alpha-synuclein), PARK2 (parkin RBR E3 ubiquitin protein ligase), chromosome 22q11 deletion/DiGeorge region, and FMR1 (fragile X mental retardation 1) repeat expansion, which influence the development of both ASD and PD, with converging features related to synaptic function and neurogenesis. Both PD and ASD display alterations and impairments at the synaptic level, representing early and key disease phenotypes, which support the hypothesis of converging mechanisms between the two types of diseases. Therefore, understanding the underlying molecular mechanisms might inform on common targets and therapeutic approaches. We propose to re-conceptualize how we understand these disorders and provide a new angle into disease targets and mechanisms linking neurodevelopmental disorders and neurodegeneration.
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Maltsev AV, Borodina YV, Skuratovskaya LN, Kukharsky MS, Ovchinnikov RK, Razinskaya OD, Smirnov AP, Kovrazhkina EA, Ustyugov AA. [The association of gamma-synuclein autoantibodies with the polymorphism in exon 4 of the coding gene]. Zh Nevrol Psikhiatr Im S S Korsakova 2018; 118:68-70. [PMID: 30335075 DOI: 10.17116/jnevro201811809168] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
AIM To analyze the polymorphism in exon 4 of the gamma-synuclein gene (SNCG) in patients with autoantibodies against the gamma-synuclein protein. MATERIAL AND METHODS To identify autoantibodies against gamma-synuclein, the serum from patients with chronic cerebral ischemia and cervical osteochondrosis was used. All patients were women of the Slavic ethnic group, mean age 61±5 years. The isolated genomic DNA was used to determine the point mutation in exon 4 by the restriction endonuclease HphI and subsequent sequencing of the resulting fragments to confirm the results. RESULTS AND CONCLUSION Antibodies against gamma-synuclein were identified in 2 patients with chronic cerebral ischemia and 3 with cervical osteochondrosis. All five patients had a T to A substitution at position 371, which was detected by the restriction endonuclease HphI resulting in a hydrolysis of the amplicon and the formation of two fragments. The subsequent sequencing of exon 4 of the SNCG revealed no other mutations and confirmed the T to A substitution. This single nucleotide polymorphism results in the amino acid substitution of glutamic acid to valine at position 110 (out of 127), changing its physicochemical properties and the ability to form aggregates as well as post-translational modifications. The obtained results provide grounds for further association studies of SNCG polymorphism in patients with various diseases of the nervous system.
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Affiliation(s)
- A V Maltsev
- Institute of Physiologically Active Compounds RAS, Chernogolovka, Russia
| | - Yu V Borodina
- Hospital Scentific Center RAS, Chernogolovka, Russia
| | - L N Skuratovskaya
- Research Institute of General Pathology and Pathophysiology, Moscow, Russia
| | - M S Kukharsky
- Institute of Physiologically Active Compounds RAS, Chernogolovka, Russia
| | - R K Ovchinnikov
- Institute of Physiologically Active Compounds RAS, Chernogolovka, Russia; Pirogov Russian National Research Medical University, Moscow, Russia
| | - O D Razinskaya
- Pirogov Russian National Research Medical University, Moscow, Russia
| | - A P Smirnov
- Pirogov Russian National Research Medical University, Moscow, Russia
| | - E A Kovrazhkina
- Pirogov Russian National Research Medical University, Moscow, Russia
| | - A A Ustyugov
- Institute of Physiologically Active Compounds RAS, Chernogolovka, Russia
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Abstract
α-Synuclein is an abundant neuronal protein that is highly enriched in presynaptic nerve terminals. Genetics and neuropathology studies link α-synuclein to Parkinson's disease (PD) and other neurodegenerative disorders. Accumulation of misfolded oligomers and larger aggregates of α-synuclein defines multiple neurodegenerative diseases called synucleinopathies, but the mechanisms by which α-synuclein acts in neurodegeneration are unknown. Moreover, the normal cellular function of α-synuclein remains debated. In this perspective, we review the structural characteristics of α-synuclein, its developmental expression pattern, its cellular and subcellular localization, and its function in neurons. We also discuss recent progress on secretion of α-synuclein, which may contribute to its interneuronal spread in a prion-like fashion, and describe the neurotoxic effects of α-synuclein that are thought to be responsible for its role in neurodegeneration.
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Affiliation(s)
- Jacqueline Burré
- Appel Institute for Alzheimer's Disease Research, Brain and Mind Research Institute, Weill Cornell Medicine, New York, New York 10021
| | - Manu Sharma
- Appel Institute for Alzheimer's Disease Research, Brain and Mind Research Institute, Weill Cornell Medicine, New York, New York 10021
| | - Thomas C Südhof
- Departments of Molecular and Cellular Physiology, Stanford University Medical School, Stanford, California 94305
- Howard Hughes Medical Institute, Stanford University Medical School, Stanford, California 94305
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Uversky VN. Looking at the recent advances in understanding α-synuclein and its aggregation through the proteoform prism. F1000Res 2017; 6:525. [PMID: 28491292 PMCID: PMC5399969 DOI: 10.12688/f1000research.10536.1] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/13/2017] [Indexed: 12/31/2022] Open
Abstract
Despite attracting the close attention of multiple researchers for the past 25 years, α-synuclein continues to be an enigma, hiding sacred truth related to its structure, function, and dysfunction, concealing mechanisms of its pathological spread within the affected brain during disease progression, and, above all, covering up the molecular mechanisms of its multipathogenicity, i.e. the ability to be associated with the pathogenesis of various diseases. The goal of this article is to present the most recent advances in understanding of this protein and its aggregation and to show that the remarkable structural, functional, and dysfunctional multifaceted nature of α-synuclein can be understood using the proteoform concept.
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Affiliation(s)
- Vladimir N Uversky
- Department of Molecular Medicine and USF Health Byrd Alzheimer's Research Institute, Morsani College of Medicine, University of South Florida, 12901 Bruce B. Downs Blvd. MDC07, Tampa, FL, 33620, USA.,Laboratory of New Methods in Biology, Institute for Biological Instrumentation, Russian Academy of Sciences, 7 Institutskaya St., 142290 Pushchino, Moscow Region, Russian Federation.,Laboratory of Structural Dynamics, Stability and Folding Of Proteins, Institute of Cytology, Russian Academy of Sciences, 4 Tikhoretsky Av., 194064 St. Petersburg, Russian Federation
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Abstract
In 2017, it is two hundred years since James Parkinson provided the first complete clinical description of the disease named after him, fifty years since the introduction of high-dose D,L-DOPA treatment and twenty years since α-synuclein aggregation came to the fore. In 1998, multiple system atrophy joined Parkinson's disease and dementia with Lewy bodies as the third major synucleinopathy. Here we review our work, which led to the identification of α-synuclein in Lewy bodies, Lewy neurites and Papp-Lantos bodies, as well as what has happened since. Some of the experiments described were carried out in collaboration with ML Schmidt, JQ Trojanowski and VMY Lee.
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Affiliation(s)
| | - Ross Jakes
- MRC Laboratory of Molecular Biology, Cambridge, UK
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Tolmasov M, Djaldetti R, Lev N, Gilgun-Sherki Y. Pathological and clinical aspects of alpha/beta synuclein in Parkinson's disease and related disorders. Expert Rev Neurother 2016; 16:505-13. [PMID: 26959397 DOI: 10.1586/14737175.2016.1164600] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Parkinson's disease (PD) and related synucleinopathies are characterized by extensive neuronal cell loss, which is potentially triggered by α-synuclein misfolding and aggregation. Therefore it is reasonable to suggest that treatments targeting α-synuclein could reduce its levels and toxicity, rescue neuronal cells and halt the neurodegeneration process. Several approaches to decrease α-synuclein levels were employed thus far, mainly by using β-synuclein, another protein from the same family, or immunotherapies. These treatments demonstrated some positive results in preclinical studies, which may pave the road to the development of new promising disease-modifying therapies (DMTs). This approach should be further examined in preclinical and clinical settings, together with a clear process in order to advance candidates, enable the ability to define when there are target engagements and to detect what is a meaningful pharmacological response, and how it will be translated in clinical efficacy.
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Affiliation(s)
- Michael Tolmasov
- a Specialty Products Department , Dexcel Pharma Technologies Ltd ., Jerusalem , Israel
| | - Ruth Djaldetti
- b Department of Neurology , Rabin Medical Center, Beilinson Campus , Petach Tikva , Israel
| | - Nirit Lev
- b Department of Neurology , Rabin Medical Center, Beilinson Campus , Petach Tikva , Israel
| | - Yossi Gilgun-Sherki
- a Specialty Products Department , Dexcel Pharma Technologies Ltd ., Jerusalem , Israel
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12
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Cheng JC, Chiang MT, Lee CH, Liu SY, Chiu KC, Chou YT, Huang RY, Huang SM, Shieh YS. γ-Synuclein Expression Is a Malignant Index in Oral Squamous Cell Carcinoma. J Dent Res 2015; 95:439-45. [PMID: 26661712 DOI: 10.1177/0022034515621728] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Dysregulation of γ-synuclein (SNCG) has been reported in many cancers; however, its role in cancer development is still controversial. Here, we examined the potential involvement of DNA methylation in regulating SNCG and its role in oral squamous cell carcinoma (OSCC). We used 8 OSCC cell lines to investigate SNCG methylation and expression. SNCG methylation was examination by methylation-specific polymerase chain reaction and bisulfate sequencing. Cells showing a high degree of SNCG methylation were treated with 5-aza (methylation inhibitor), and changes in their methylation and expression profiles were analyzed. Functional effects of SNCG in OSCC were examined by its overexpression and knockdown. Additionally, methylation and expression of SNCG in OSCC tissues were investigated and correlated with clinicopathologic features. All OSCC cells showed detectable SNCG expression at the mRNA and protein levels. Methylation-specific polymerase chain reaction and bisulfate sequencing revealed high SNCG expression in SCC25 cells with the unmethylated allele, and their 15 CpG islands were unmethylated. The methylated allele was detected only in OEC-M1 cells exhibiting low SNCG expression, and their CpG islands were partially methylated. 5-aza treatment in OEC-M1 cells attenuated methylation and restored SNCG expression. SNCG overexpression increased colony forming, migration, and invasion abilities in OEC-M1 cells. Silencing SNCG in SCC25 cells suppressed these behaviors. All 25 tumor-adjacent normal tissues were negative for SNCG immunostaining. SNCG upregulation was frequently observed in dysplastic and OSCC tissues. Positive SNCG expression was found in 45% (37 of 82) OSCC tissues. Positive SNCG expression in OSCC significantly correlated with cancer staging and lymph node metastasis. However, SNCG methylation did not correlate with its expression and clinicopathologic variables in OSCC tissues. DNA methylation may participate in regulating SNCG expression in some OSCC cells. SNCG upregulation could be involved in OSCC progression.
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Affiliation(s)
- J C Cheng
- Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan Oral Maxillofacial Surgery Department, Cardinal Tien Hospital, New Taipei City, Taiwan
| | - M T Chiang
- Department of Dentistry, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - C H Lee
- Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - S Y Liu
- Department of Oral and Maxillofacial Surgery, Chi Mei Medical Center, Tainan. Taiwan
| | - K C Chiu
- Department of Dentistry, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Y T Chou
- Institute of Biotechnology, National Tsing Hua University, Hsinchu, Taiwan
| | - R Y Huang
- Department of Dentistry, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - S M Huang
- Department of Biochemistry, National Defense Medical Center, Taipei, Taiwan
| | - Y S Shieh
- Department of Dentistry, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
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13
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Abstract
α-Synuclein is an abundant neuronal protein which localizes predominantly to presynaptic terminals, and is strongly linked genetically and pathologically to Parkinson's disease and other neurodegenerative diseases. While the accumulation of α-synuclein in the form of misfolded oligomers and large aggregates defines multiple neurodegenerative diseases called "synucleinopathies", its cellular function has remained largely unclear, and is the subject of intense investigation. In this review, I focus on the structural characteristics of α-synuclein, its cellular and subcellular localization, and discuss how this relates to its function in neurons, in particular at the neuronal synapse.
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Affiliation(s)
- Jacqueline Burré
- Appel Institute for Alzheimer’s Disease Research, Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY, USA
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14
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Peters OM, Shelkovnikova T, Highley JR, Cooper-Knock J, Hortobágyi T, Troakes C, Ninkina N, Buchman VL. Gamma-synuclein pathology in amyotrophic lateral sclerosis. Ann Clin Transl Neurol 2014; 2:29-37. [PMID: 25642432 PMCID: PMC4301672 DOI: 10.1002/acn3.143] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2014] [Revised: 10/16/2014] [Accepted: 10/17/2014] [Indexed: 12/12/2022] Open
Abstract
Objective The prominent histopathological feature of the amyotrophic lateral sclerosis (ALS) is the presence of intracellular inclusions in degenerating neurons and their axons. The appearance and localization of these pathological structures depend on an aggregated protein that forms their scaffold. We investigated if γ-synuclein, an aggregation-prone protein highly expressed in healthy motor neurons, and predominantly localized in their axons and synaptic terminals is involved in ALS pathology. Methods Immunostaining of histological sections and sequential protein extraction from postmortem neural samples followed by immunoblotting. Results Immunohistochemical screening revealed a subset of sporadic (9 of 31) and familial (8 of 23) ALS cases with a novel type of pathology characterized by the accumulation of γ-synuclein in distinct profiles within the dorsolateral column. Sequential fractionation of proteins from the spinal cord tissues revealed detergent-insoluble γ-synuclein species specifically in the dorsolateral corticospinal tracts of a ALS patient with γ-synuclein-positive profiles in this region. These profiles are negative for protein markers commonly found in pathological inclusions in the spinal cord of ALS patients and most probably represent degenerated axons of upper motor neurons that have lost their neurofilaments. A subset of these profiles was found in association with phagocytic cells positive for Mac-2/Galectin-3. A smaller subset of studied ALS cases (4 of 54) contained large cytoplasmic inclusions in the cell body of remaining spinal motor neurons. Interpretation Our observations suggest that pathological aggregation of γ-synuclein might contribute to the pathogenesis of ALS.
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Affiliation(s)
- Owen M Peters
- School of Biosciences, Cardiff University Museum Avenue, Cardiff, CF10 3AX, United Kingdom
| | - Tatyana Shelkovnikova
- School of Biosciences, Cardiff University Museum Avenue, Cardiff, CF10 3AX, United Kingdom
| | - John Robin Highley
- The Sheffield Institute for Translational Neuroscience 385A Glossop Road, Sheffield, S10 2HQ, United Kingdom
| | - Johnathan Cooper-Knock
- The Sheffield Institute for Translational Neuroscience 385A Glossop Road, Sheffield, S10 2HQ, United Kingdom
| | - Tibor Hortobágyi
- Department of Clinical Neuroscience and MRC London Neurodegenerative Diseases Brain Bank, Institute of Psychiatry, King's College London De Crespigny Park, London, SE5 8AF, United Kingdom
| | - Claire Troakes
- Department of Clinical Neuroscience and MRC London Neurodegenerative Diseases Brain Bank, Institute of Psychiatry, King's College London De Crespigny Park, London, SE5 8AF, United Kingdom
| | - Natalia Ninkina
- School of Biosciences, Cardiff University Museum Avenue, Cardiff, CF10 3AX, United Kingdom ; Institute of General Pathology and Pathophysiology of Russian Academy of Medical Science 8 Baltijskaya str, Moscow, 125315, Russia
| | - Vladimir L Buchman
- School of Biosciences, Cardiff University Museum Avenue, Cardiff, CF10 3AX, United Kingdom
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15
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Tastekin D, Kargin S, Karabulut M, Yaldız N, Tambas M, Gurdal N, Tatli AM, Arslan D, Gok AFK, Aykan F. Synuclein-gamma predicts poor clinical outcome in esophageal cancer patients. Tumour Biol 2014; 35:11871-11877. [PMID: 25142230 DOI: 10.1007/s13277-014-2429-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2014] [Accepted: 07/31/2014] [Indexed: 02/05/2023] Open
Abstract
The synuclein gamma (SNCG) protein, a member of neuronal protein family synuclein, has been considered as a promising potential biomarker as an indicator of cancer stage and survival in patients with cancer. The present study was conducted to evaluate the prognostic value of SNCG in patients with esophageal carcinoma (EC). SNCG levels were assessed immunohistochemically in cancer tissues from 73 EC patients. Median age was 57 (range, 29-78) years old. Forty-seven percent of the patients were male. Thirty-seven percent of the patients had upper or middle localized tumor whereas 59 % had epidermoid carcinoma. More than half of the patients (61 %) had undergone operation where 57 % received adjuvant treatment including chemotherapy or chemotherapy plus radiotherapy. Median overall survival was 11.3 ± 1.8 months (95% confidence interval (CI): 7.7-14.9 months). SNCG positivity was significantly associated with the histological type of EC and inoperability (for SNCG positive vs. negative group; epidermoid 80 vs. 53 %; p = 0.05 and inoperable 59 vs.32 %; p = 0.04, respectively). Lymph node metastasis, inoperability and receiving no adjuvant treatment had significantly adverse effect on survival in the univariate analysis (p = 0.01, p < 0.001, and p = 0.001, respectively). SNCG positivity had significantly adverse effect on survival in both univariate and multivariate analysis (p = 0.02 and p = 0.01, respectively). Our results are the first to suggest that SNCG is a new independent predictor for poor prognosis in EC patients in the literature.
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Affiliation(s)
- Didem Tastekin
- Department of Medical Oncology, Oncology Institute, Istanbul University, 34390, Istanbul, Turkey,
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16
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Lytkina OA, Tarasova TV, Khritankova IV, Anokhin PK, Kukharsky MS, Ustyugov AA, Bachurin SO. Gamma-synuclein binds synaptic vesicles but does not interact with SNARE-complex proteins. DOKL BIOCHEM BIOPHYS 2014; 456:108-10. [PMID: 24993968 DOI: 10.1134/s1607672914030089] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2014] [Indexed: 11/23/2022]
Affiliation(s)
- O A Lytkina
- Institute of Physiologically Active Substances, Russian Academy of Sciences, Chernogolovka, Moscow region, Russia,
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17
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Yuan J, Zhao Y. Evolutionary aspects of the synuclein super-family and sub-families based on large-scale phylogenetic and group-discrimination analysis. Biochem Biophys Res Commun 2013; 441:308-17. [PMID: 24140056 DOI: 10.1016/j.bbrc.2013.09.132] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2013] [Accepted: 09/29/2013] [Indexed: 01/22/2023]
Abstract
Over the last decade, many genetic studies have suggested that the synucleins, which are small, natively unfolded proteins, are closely related to Parkinson's disease and cancer. Less is known about the molecular basis of this role. A comprehensive analysis of the evolutionary path of the synuclein protein family may reveal the relationship between evolutionarily conserved residues and protein function or structure. The phylogeny of 252 unique synuclein sequences from 73 organisms suggests that gamma-synuclein is the common ancestor of alpha- and beta-synuclein. Although all three sub-families remain highly conserved, especially at the N-terminal, nearly 15% of the residues in each sub family clearly diverged during evolution, providing crucial guidance for investigations of the different properties of the members of the superfamily. His50 is found to be an alpha-specific conserved residue (91%) and, based on mutagenesis, evolutionarily developed a secondary copper binding site in the alpha synuclein family. Surprisingly, this site is located between two well-known polymorphisms of alpha-synuclein, E46K and A53T, which are linked to early-onset Parkinson's disease, suggesting that the mutation-induced impairment of copper binding could be a mechanism responsible for alpha-synuclein aggregation.
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Affiliation(s)
- Jiawen Yuan
- Department of Neurology, Shanghai Sixth People's Hospital affiliated to Shanghai Jiao Tong University, Shanghai 200233, China
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18
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Surgucheva I, Gunewardena S, Rao HS, Surguchov A. Cell-specific post-transcriptional regulation of γ-synuclein gene by micro-RNAs. PLoS One 2013; 8:e73786. [PMID: 24040069 PMCID: PMC3770685 DOI: 10.1371/journal.pone.0073786] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2013] [Accepted: 07/28/2013] [Indexed: 11/18/2022] Open
Abstract
γ-Synuclein is a member of the synucleins family of small proteins, which consists of three members:α, β- and γ-synuclein. γ-Synuclein is abnormally expressed in a high percentage of advanced and metastatic tumors, but not in normal or benign tissues. Furthermore, γ-synuclein expression is strongly correlated with disease progression, and can stimulate proliferation, induce invasion and metastasis of cancer cells. γ-Synuclein transcription is regulated basically through the binding of AP-1 to specific sequences in intron 1. Here we show that γ-synuclein expression may be also regulated by micro RNAs (miRs) on post-transcriptional level. According to prediction by several methods, the 3′-untranslated region (UTR) of γ-synuclein gene contains targets for miRs. Insertion of γ-synuclein 3′-UTR downstream of the reporter luciferase (LUC) gene causes a 51% reduction of LUC activity after transfection into SKBR3 and Y79 cells, confirming the presence of efficient targets for miRs in this fragment. Expression of miR-4437 and miR-4674 for which putative targets in 3′-UTR were predicted caused a 61.2% and 60.1% reduction of endogenous γ-synuclein expression confirming their role in gene expression regulation. On the other hand, in cells overexpressing γ-synuclein no significant effect of miRs on γ-synuclein expression was found suggesting that miRs exert their regulatory effect only at low or moderate, but not at high level of γ-synuclein expression. Elevated level of γ-synuclein differentially changes the level of several miRs expression, upregulating the level of some miRs and downregulating the level of others. Three miRs upregulated as a result of γ-synuclein overexpression, i.e., miR-885-3p, miR-138 and miR-497 have putative targets in 3′-UTR of the γ-synuclein gene. Some of miRs differentially regulated by γ-synuclein may modulate signaling pathways and cancer related gene expression. This study demonstrates that miRs might provide cell-specific regulation of γ-synuclein expression and set the stage to further evaluate their role in pathophysiological processes.
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Affiliation(s)
- Irina Surgucheva
- Retinal Biology Research Laboratory, Veterans Administration Medical Center, Kansas City, Missouri, United States of America
- Department of Neurology, Kansas University Medical Center, Kansas City, Kansas, United States of America
| | - Sumedha Gunewardena
- Department of Molecular and Integrative Physiology, Kansas University Medical Center, Kansas City, Kansas, United States of America
| | - H. Shanker Rao
- Department of Molecular and Integrative Physiology, Kansas University Medical Center, Kansas City, Kansas, United States of America
| | - Andrei Surguchov
- Retinal Biology Research Laboratory, Veterans Administration Medical Center, Kansas City, Missouri, United States of America
- Department of Neurology, Kansas University Medical Center, Kansas City, Kansas, United States of America
- * E-mail:
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19
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Wan F, Dong L, Zhang F, Wang Y, Chen F, Ni S, Chen Y, Long J. Clinical study of the relationship between γ-synuclein and the response of neoadjuvant chemotherapy in breast cancer. J Int Med Res 2013; 41:743-753. [PMID: 23696593 DOI: 10.1177/0300060513484434] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
OBJECTIVES To investigate relationships between several protein biomarkers and clinical responses to neoadjuvant chemotherapy (NAC) in breast cancer. METHODS Tumour tissue samples from female patients with locally advanced breast carcinoma (stages IIA to IIIC), treated with NAC regimens (including 5-fluorouracil, epirubicin, cyclophosphamide and docetaxel, epirubicin, cyclophosphamide) were analysed retrospectively. Immunohistochemical analysis was used to test for protein levels of oestrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor (HER)-2, protein 53 (p53) and γ-synuclein. Relationships between protein biomarkers and responses to NAC were analysed by multivariate logistic regression analysis. RESULTS Data from 154 patients (median age, 51 years; range 27-75 years) were included. Multivariate logistic regression analysis showed that γ-synuclein was an independent predictor of NAC objective response rate, and a statistically significant relationship was observed between NAC regimen, γ-synuclein levels and pathological complete response rate. CONCLUSIONS These study findings suggest that γ-synuclein - in combination with other markers such as ER, PR and HER-2 - may serve as a biomarker for response to NAC in breast cancer and warrants further study.
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Affiliation(s)
- Fan Wan
- Department of Surgery, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, China
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20
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Surguchov A. Synucleins: are they two-edged swords? J Neurosci Res 2012; 91:161-6. [PMID: 23150342 DOI: 10.1002/jnr.23149] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2012] [Revised: 08/10/2012] [Accepted: 09/07/2012] [Indexed: 12/22/2022]
Abstract
The synuclein family consists of three distinct highly homologous genes, α-synuclein, β-synuclein, and γ-synuclein, which have so far been found only in vertebrates. Proteins encoded by these genes are characterized by an acidic C-terminal region and five or six imperfect repeat motifs (KTKEGV) distributed throughout the highly conserved N-terminal region. Numerous data demonstrate that synucleins are implicated in two groups of the most devastating human disorders, i.e., neurodegenerative diseases (NDDs) and cancer. Mutations in the α-synuclein gene are associated with familial forms of Parkinson's disease (PD), and accumulation of α-synuclein inclusions is a hallmark of this disorder. In breast cancer, increased expression of γ-synuclein correlates with disease progression. Conversely, some results indicate that the members of the synuclein family may have a protective effect. How might these small proteins combine such controversial properties? We present evidence that synuclein's features are basically regulated by two mechanisms, i.e., posttranslational modifications (PTMs) and the level of their expression. We also discuss a new, emerging area of investigation of synucleins, namely, their role in the cell-to-cell propagation of pathology.
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21
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Ninkina N, Peters OM, Connor-Robson N, Lytkina O, Sharfeddin E, Buchman VL. Contrasting effects of α-synuclein and γ-synuclein on the phenotype of cysteine string protein α (CSPα) null mutant mice suggest distinct function of these proteins in neuronal synapses. J Biol Chem 2012; 287:44471-7. [PMID: 23129765 PMCID: PMC3531760 DOI: 10.1074/jbc.m112.422402] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
In neuronal synapses, neurotransmitter-loaded vesicles fuse with presynaptic plasma membrane in a complex sequence of tightly regulated events. The assembly of specialized SNARE complexes plays a pivotal role in this process. The function of the chaperone cysteine string protein α (CSPα) is important for synaptic SNARE complex formation, and mice lacking this protein develop severe synaptic dysfunction and neurodegeneration that lead to their death within 3 months after birth. Another presynaptic protein, α-synuclein, also potentiates SNARE complex formation, and its overexpression rescues the phenotype of CSPα null mutant mice, although these two proteins use different mechanisms to achieve this effect. α-Synuclein is a member of a family of three related proteins whose structural similarity suggests functional redundancy. Here, we assessed whether γ-synuclein shares the ability of α-synuclein to bind synaptic vesicles and ameliorate neurodegeneration caused by CSPα deficiency in vivo. Although the N-terminal lipid-binding domains of the two synucleins showed similar affinity for purified synaptic vesicles, the C-terminal domain of γ-synuclein was not able to interact with synaptobrevin-2/VAMP2. Consequently, overexpression of γ-synuclein did not have any noticeable effect on the phenotype of CSPα null mutant mice. Our data suggest that the functions of α- and γ-synucleins in presynaptic terminals are not fully redundant.
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Affiliation(s)
- Natalia Ninkina
- School of Biosciences, Cardiff University, Cardiff CF10 3AX, United Kingdom
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22
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Elcoroaristizabal Martín X, Gómez Busto F, González Fernández MC, de Pancorbo MM. [Role of genetics in the etiology of synucleinopathies]. Rev Esp Geriatr Gerontol 2011; 46 Suppl 1:3-11. [PMID: 22152908 DOI: 10.1016/j.regg.2011.10.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/31/2023]
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.
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Affiliation(s)
- Xabier Elcoroaristizabal Martín
- Grupo de Investigación BIOMICS, Departamento de Biología Celular A, Centro de Investigación y Estudios Avanzados Lucio Lascaray, Universidad del País Vasco UPV/EHU, Vitoria-Gasteiz, España
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23
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Maitta RW, Wolgast LR, Wang Q, Zhang H, Bhattacharyya P, Gong JZ, Sunkara J, Albanese JM, Pizzolo JG, A.Cannizzaro L, Ramesh K, Ratech H. Alpha- and beta-synucleins are new diagnostic tools for acute erythroid leukemia and acute megakaryoblastic leukemia. Am J Hematol 2011; 86:230-4. [PMID: 21264917 DOI: 10.1002/ajh.21932] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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.
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Affiliation(s)
- Robert W. Maitta
- Montefiore Medical Center /Albert Einstein College of Medicine Bronx, New York
| | - Lucia R. Wolgast
- Montefiore Medical Center /Albert Einstein College of Medicine Bronx, New York
| | - Qing Wang
- Montefiore Medical Center /Albert Einstein College of Medicine Bronx, New York
| | - Hailing Zhang
- Montefiore Medical Center /Albert Einstein College of Medicine Bronx, New York
| | | | | | - Jaya Sunkara
- Montefiore Medical Center /Albert Einstein College of Medicine Bronx, New York
| | - Joseph M. Albanese
- Montefiore Medical Center /Albert Einstein College of Medicine Bronx, New York
| | - John G. Pizzolo
- Montefiore Medical Center /Albert Einstein College of Medicine Bronx, New York
| | - Linda A.Cannizzaro
- Montefiore Medical Center /Albert Einstein College of Medicine Bronx, New York
| | - K.H. Ramesh
- Montefiore Medical Center /Albert Einstein College of Medicine Bronx, New York
| | - Howard Ratech
- Montefiore Medical Center /Albert Einstein College of Medicine Bronx, New York
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Uversky VN. Flexible Nets of Malleable Guardians: Intrinsically Disordered Chaperones in Neurodegenerative Diseases. Chem Rev 2010; 111:1134-66. [DOI: 10.1021/cr100186d] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- Vladimir N. Uversky
- Department of Molecular Medicine, University of South Florida, Tampa, Florida 33612, United States, Institute for Intrinsically Disordered Protein Research, Center for Computational Biology and Bioinformatics, University of Indiana School of Medicine, Indianapolis, Indiana 46202, United States, and Institute for Biological Instrumentation, Russian Academy of Sciences, 142292 Pushchino, Moscow Region, Russia
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Intrinsic Disorder in Proteins Associated with Neurodegenerative Diseases. PROTEIN FOLDING AND MISFOLDING: NEURODEGENERATIVE DISEASES 2008. [DOI: 10.1007/978-1-4020-9434-7_2] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Singh MN, Stringfellow HF, Taylor SE, Ashton KM, Ahmad M, Abdo KR, El-Agnaf OM, Martin-Hirsch PL, Martin FL. Elevated expression of CYP1A1 and -SYNUCLEIN in human ectopic (ovarian) endometriosis compared with eutopic endometrium. Mol Hum Reprod 2008; 14:655-63. [DOI: 10.1093/molehr/gan056] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
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Applications of novel monoclonal antibodies specific for synuclein-gamma in evaluating its levels in sera and cancer tissues from colorectal cancer patients. Cancer Lett 2008; 269:148-58. [PMID: 18586385 DOI: 10.1016/j.canlet.2008.04.037] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2008] [Revised: 04/01/2008] [Accepted: 04/22/2008] [Indexed: 11/22/2022]
Abstract
Overexpressions of synuclein-gamma (SNCG) in different cancers display stage-specific patterns. At present, appropriate anti-SNCG monoclonal antibodies (mAbs) with high specificity and affinity are unavailable for different immunoassays in clinical applications. In this study, we generated 10 mAbs against endogenous SNCG and evaluated SNCG levels in several colorectal cancer cell lines, serum samples and tumor tissues from colorectal cancer (CRC) patients. Elevated SNCG levels in cancer cell lines evaluated by a novel sandwich ELISA were consistent with data obtained from Western blot. Secreted SNCG protein levels in sera from CRC patients could be detected by the sandwich ELISA and were further confirmed by Western blot analysis following SNCG enrichment. Immunohistochemical results showed that SNCG was highly expressed in tumor cells of CRC patients, but was undetectable in the adjacent normal epithelium. Taken together, these novel anti-SNCG mAbs specifically recognized endogenous SNCG and were suitable for measuring SNCG levels in cell lysates, human serum samples, and tumor tissues. Elevated serum SNCG and overexpressed SNCG in tumor tissue from CRC patients suggest SNCG is a potential biomarker for CRC.
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Abstract
Aggregation and subsequent development of protein deposition diseases originate from conformational changes in corresponding amyloidogenic proteins. The accumulated data support the model where protein fibrillogenesis proceeds via the formation of a relatively unfolded amyloidogenic conformation, which shares many structural properties with the pre-molten globule state, a partially folded intermediate first found during the equilibrium and kinetic (un)folding studies of several globular proteins and later described as one of the structural forms of natively unfolded proteins. The flexibility of this structural form is essential for the conformational rearrangements driving the formation of the core cross-beta structure of the amyloid fibril. Obviously, molecular mechanisms describing amyloidogenesis of ordered and natively unfolded proteins are different. For ordered protein to fibrillate, its unique and rigid structure has to be destabilized and partially unfolded. On the other hand, fibrillogenesis of a natively unfolded protein involves the formation of partially folded conformation; i.e., partial folding rather than unfolding. In this review recent findings are surveyed to illustrate some unique features of the natively unfolded proteins amyloidogenesis.
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Affiliation(s)
- Vladimir N Uversky
- Department of Biochemistry and Molecular Biology, Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
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Ye Q, Zheng MH. Advances in γ-Synuclein and progression of tumors. Shijie Huaren Xiaohua Zazhi 2008; 16:1666-1671. [DOI: 10.11569/wcjd.v16.i15.1666] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
γ-Synuclein with strong tissue specificity, a member of the synuclein family, is mainly located in nervous system. Recently, elevated levels of γ-Synuclein was detected in various types of cancers, such as breast, ovarian, liver, gastric cancers, etc., especially in their advanced stages, which indicated loss of tissue specificity in cancer development and also suggested that γ-Synuclein might serve as a new tumor marker. Additionally, multiple pathways influence the regulation of γ-Synuclein expression. γ-Synuclein has also been shown to promote invasion and metastasis of breast and ovarian cancers and enhance caners' tolerance to some chemotherapies . Overexpression of γ-synuclein also interferes with drug-induced apoptotic responses, which makes it a potential target for treatment.
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Porcine γ-synuclein: molecular cloning, expression analysis, chromosomal localization and functional expression. Mol Biol Rep 2008; 36:971-9. [DOI: 10.1007/s11033-008-9270-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2008] [Accepted: 04/24/2008] [Indexed: 11/25/2022]
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31
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Retinal ganglion cells downregulate gene expression and lose their axons within the optic nerve head in a mouse glaucoma model. J Neurosci 2008; 28:548-61. [PMID: 18184797 DOI: 10.1523/jneurosci.3714-07.2008] [Citation(s) in RCA: 232] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Little is known about molecular changes occurring within retinal ganglion cells (RGCs) before their death in glaucoma. Taking advantage of the fact that gamma-synuclein (Sncg) mRNA is expressed specifically and highly in adult mouse RGCs, we show in the DBA/2J mouse model of glaucoma that there is not only a loss of cells expressing this gene, but also a downregulation of gene expression of Sncg and many other genes within large numbers of RGCs. This downregulation of gene expression within RGCs occurs together with reductions in FluoroGold (FG) retrograde transport. Surprisingly, there are also large numbers of Sncg-expressing cells without any FG labeling, and among these many that have a marker previously associated with disconnected RGCs, accumulation of phosphorylated neurofilaments in their somas. These same diseased retinas also have large numbers of RGCs that maintain the intraocular portion while losing the optic nerve portion of their axons, and these disconnected axons terminate within the optic nerve head. Our data support the view that RGC degeneration in glaucoma has two separable stages: the first involves atrophy of RGCs, whereas the second involves an insult to axons, which causes the degeneration of axon portions distal to the optic nerve head but does not cause the immediate degeneration of intraretinal portions of axons or the immediate death of RGCs.
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Gu YM, Tan JX, Lu XW, Ding Y, Han X, Sun YJ. BCSG1 Methylation Status and BCSG1 Expression in Breast Tissues Derived from Chinese Women with Breast Cancer. Oncology 2008; 74:61-8. [DOI: 10.1159/000139125] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2008] [Accepted: 04/15/2008] [Indexed: 01/29/2023]
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Chapter 6 Molecular and Cellular Biology of Synucleins. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2008; 270:225-317. [DOI: 10.1016/s1937-6448(08)01406-8] [Citation(s) in RCA: 80] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Yuan Z, Zhao X, Yan F, Zhao J, Liu H, Xiong S, Li J, Chen L, Wei Y. Beta-synuclein protein from Xenopus laevis: overexpression in Escherichia coli of the GST-tagged protein and production of polyclonal antibodies. BIOCHEMISTRY. BIOKHIMIIA 2007; 72:1270-1278. [PMID: 18205611 DOI: 10.1134/s0006297907110144] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/25/2023]
Abstract
This report presents a procedure to obtain and purify recombinant beta-synuclein from Xenopus laevis expressed in Escherichia coli as a glutathione-S-transferase fusion protein. After identification by mass spectrometry, the protein was then used to raise anti-X. laevis beta-synuclein polyclonal antibodies, which were suitable to detect the presence of beta-synuclein in X. laevis brain by Western blot. This is the first report of a positive identification of beta-synuclein in an amphibian at the protein level.
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Affiliation(s)
- Zhu Yuan
- State Key Laboratory of Biotherapy, West China Hospital, West China Medical School and College of Life Science, Sichuan University, Chengdu, Sichuan, 610041, China
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Ahmad M, Attoub S, Singh MN, Martin FL, El-Agnaf OMA. Gamma-synuclein and the progression of cancer. FASEB J 2007; 21:3419-30. [PMID: 17567567 DOI: 10.1096/fj.07-8379rev] [Citation(s) in RCA: 80] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
The synucleins are a small, soluble, highly conserved group of neuronal proteins that have been implicated in both neurodegenerative diseases and cancer. The synuclein family consists of alpha-, beta-, and gamma-synucleins (gamma-syn). They are a natively unfolded group of proteins that share sequence homologies and structural properties. So far, the biological functions of the synucleins are still unclear, but their involvement in neurodegenerative diseases and cancer may provide insights into the pathological processes that result from these two groups of debilitating diseases, and present the possibility to use them as potential targets for early diagnosis and treatment. Recently, elevated levels of gamma-syn proteins have been detected in various types of cancer, especially in advanced stages of the disease. Furthermore, studies to date indicate that overexpression of gamma-syn compromises normal mitotic checkpoint controls, resulting in multinucleation as well as faster cell growth. Gamma-syn has also been shown to promote invasion and metastasis in in vitro assays as well as in animal models. Overexpression of gamma-syn also interferes with drug-induced apoptotic responses. These observations raise questions about the involvement of gamma-syn in the process of tumorigenesis and metastasis, and efforts have already been made to use gamma-syn as a marker for assessing breast cancer progression. This review will discuss the involvement of gamma-syn in cancer progression, metastasis and its potential as a marker.
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Affiliation(s)
- Mushfika Ahmad
- Department of Biochemistry, Faculty of Medicine and Health Sciences, United Arab Emirates, Al Ain, PO BOX 17666, United Arab Emirates
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Papachroni KK, Ninkina N, Papapanagiotou A, Hadjigeorgiou GM, Xiromerisiou G, Papadimitriou A, Kalofoutis A, Buchman VL. Autoantibodies to alpha-synuclein in inherited Parkinson's disease. J Neurochem 2007; 101:749-56. [PMID: 17448146 PMCID: PMC3154646 DOI: 10.1111/j.1471-4159.2006.04365.x] [Citation(s) in RCA: 130] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Neurodegeneration in Parkinson's disease (PD) is accompanied by a local immune reaction in the affected brain regions. It is well established that alpha-synuclein is directly implicated in the pathogenesis of PD. Development of the disease is often associated with changes of expression and cellular compartmentalisation of this protein; moreover, its oligomers or protofibrils are often released to the CSF and plasma of patients. Aggregated alpha-synuclein can trigger the activation of microglia; however, its capacity to induce production of specific autoantibodies (AAb) has not been assessed. In this study, we examined the presence of AAb against synuclein family members in the peripheral blood serum of PD patients and control individuals. Presence of AAb against beta-synuclein or gamma-synuclein showed no association with PD. Multi-epitopic AAb against alpha-synuclein were detected in 65% of all patients tested and their presence strongly correlated with an inherited mode of the disease but not with other disease-related factors. The frequency of the presence of AAb in the studied group of patients with sporadic form of PD was not significantly different from the frequency in the control group but very high proportion (90%) of patients with familial form of the disease were positive for AAb against alpha-synuclein. We hypothesise that these AAb could be involved in pathogenesis of the inherited form of PD.
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Affiliation(s)
- Katerina K Papachroni
- Laboratory of Biological Chemistry, University of Athens Medical School, Athens, Greece
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37
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Kuhn M, Haebig K, Bonin M, Ninkina N, Buchmann VL, Poths S, Riess O. Whole genome expression analyses of single- and double-knock-out mice implicate partially overlapping functions of alpha- and gamma-synuclein. Neurogenetics 2007; 8:71-81. [PMID: 17318638 PMCID: PMC3306239 DOI: 10.1007/s10048-007-0079-z] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2006] [Accepted: 01/22/2007] [Indexed: 02/04/2023]
Abstract
alpha-Synuclein has been implicated in the pathogenesis of Parkinson's disease. The function of alpha-synuclein has not been deciphered yet; however, it might play a role in vesicle function, transport, or as a chaperone. alpha-Synuclein belongs to a family of three proteins, which includes beta- and gamma-synuclein. gamma-Synuclein shares 60% similarity with alpha-synuclein. Similar to alpha-synuclein, a physiological function for gamma-synuclein has not been defined yet, but it has been implicated in tumorgenesis and neurodegeneration. Interestingly, neither alpha- (SNCA(-/-)), gamma- (SNCG(-/-)), nor alpha/gamma- (SNCA_G(-/-)) deficient mice are present with any obvious phenotype. Using microarray analysis, we thus investigated whether deficiency of alpha- and gamma-synuclein leads to similar compensatory mechanisms at the RNA level and whether similar transcriptional signatures are altered in the brain. Sixty-five genes were differentially expressed in all mice. SNCA(-/-) mice and SNCG(-/-) mice shared 84 differentially expressed genes, SNCA(-/-) and SNCA_G(-/-) expressed 79 genes, and SNCG(-/-) and SNCA_G(-/-) expressed 148 genes. For many of the physiological pathways such as dopamine receptor signaling (down-regulated), cellular development, nervous system function, and cell death (up-regulated), we found groups of genes that were similarly altered in SNCA(-/-) and SNCG(-/-) mice. In one of the pathways altered in both models, we found Mapk1 as the core transcript. Other gene groups, however, such as TGF-beta signaling and apoptosis pathways genes were significantly up-regulated in the SNCA(-/-) mice but down-regulated in SNCG(-/-) mice. beta-synuclein expression was not significantly altered in any of the models.
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Affiliation(s)
- Melanie Kuhn
- Department of Medical Genetics, University of Tuebingen, 72076 Tuebingen, Germany
| | - Karina Haebig
- Department of Medical Genetics, University of Tuebingen, 72076 Tuebingen, Germany
- Microarray Facility, University of Tuebingen, 72076 Tuebingen, Germany
| | - Michael Bonin
- Department of Medical Genetics, University of Tuebingen, 72076 Tuebingen, Germany
- Microarray Facility, University of Tuebingen, 72076 Tuebingen, Germany
| | - Natalia Ninkina
- School of Biosciences, Cardiff University, Cardiff CF10 3US, UK
| | | | - Sven Poths
- Department of Medical Genetics, University of Tuebingen, 72076 Tuebingen, Germany
- Microarray Facility, University of Tuebingen, 72076 Tuebingen, Germany
| | - Olaf Riess
- Department of Medical Genetics, University of Tuebingen, 72076 Tuebingen, Germany
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38
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Kim SR, Choi WH, Park JH, Nam ES, Cho SJ, Park CH. The γ-Synuclein Expression in Breast Cancer and its Correlation with the Expression of the HER-2/neu Gene. J Breast Cancer 2007. [DOI: 10.4048/jbc.2007.10.2.114] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Affiliation(s)
- Seong Rae Kim
- Department of Surgery, Hallym University College of Medicine, Seoul, Korea
| | - Won Hyuk Choi
- Department of Surgery, Hallym University College of Medicine, Seoul, Korea
| | - Jun Ho Park
- Department of Surgery, Hallym University College of Medicine, Seoul, Korea
| | - Eun Sook Nam
- Department of Pathology, Hallym University College of Medicine, Seoul, Korea
| | - Seong Jin Cho
- Department of Pathology, Hallym University College of Medicine, Seoul, Korea
| | - Chan Heun Park
- Department of Surgery, Hallym University College of Medicine, Seoul, Korea
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Lu A, Li Q, Liu J. Regulatory mechanisms for abnormal expression of the human breast cancer specific gene 1 in breast cancer cells. ACTA ACUST UNITED AC 2006; 49:403-8. [PMID: 16989287 DOI: 10.1007/s11427-006-2006-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
Breast cancer-specific gene 1 (BCSG1), also referred as synuclein y, was originally isolated from a human breast cancer cDNA library and the protein is mainly localized to presynaptic terminals in the nervous system. BCSG1 is not expressed in normal or benign breast lesions, but expressed at an extremely high level in the vast majority of the advanced staged breast carcinomas and ovarian carcinomas. Overexpression of BCSG1 in cancer cells led to significant increase in cell proliferation, motility and invasiveness, and metastasis. To elucidate the molecular mechanism and regulation for abnormal transcription of BCSG1, a variety of BCSG1 promoter luciferase reporters were constructed including 3' end deleted sequences, Sp1 deleted, and activator protein-1 (AP1) domains mutated. Transient transfection assay was used to detect the transcriptional activation of BCSG1 promoters. Results showed that the Sp1 sequence in 5'-flanking region was involved in the basal transcriptional activities of BCSG1 without cell-type specificity. In comparison to pGL3-1249, the reporter activities of pGL3-1553 in BCSG1-negative MCF-7 cells and pGL3-1759 in HepG2 cells were notably decreased. Mutations at AP1 sites in BCSG1 intron 1 significantly reduced the promoter activity in all cell lines. Transcription factors, c-jun, c-fos and cyclin AMP-responsive element binding (CREB) protein, could markedly enhance the promoter activities. Thus, our results suggest that the abnormal expression of BCSG1 in breast cancer cells is likely regulated by multiple mechanisms. The 5' flanking region of BCSG1 provides the basal transcriptional activity without cell type specificity. A critical promoter element involved in abnormal expression of BCSG1 presents in the first exon. The cell type specificity of BCSG1 transcription is probably affected through intronic cis-regulatory sequences. AP1 domains in the first intron play an important role in control of BCSG1 transcription.
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Affiliation(s)
- Aiping Lu
- Department of Pathology, Peking University School of Oncology, Beijing Cancer Hospital, Beijing 100036, China.
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40
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Liu YE, Pu W, Jiang Y, Shi D, Dackour R, Shi YE. Chaperoning of estrogen receptor and induction of mammary gland proliferation by neuronal protein synuclein gamma. Oncogene 2006; 26:2115-25. [PMID: 17016445 DOI: 10.1038/sj.onc.1210000] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Synucleins are emerging as central players in the formation of pathologically insoluble deposits characteristic of neurodegenerative diseases. However, synuclein gamma (SNCG), previously identified as a breast cancer specific gene (BCSG1), is also highly associated with breast cancer progression. Using transgenic mouse model, we demonstrated a role of SNCG in induction of highly proliferative pregnancy-like phenotype of mammary epithelial cells and branching morphology. SNCG participated in the heat shock protein-based multiprotein chaperone complex for steroid receptor signaling. Expression of SNCG in mammary epithelium resulted in a significant stimulation of ERalpha transcriptional activity. SNCG-induced mammary gland proliferation can be effectively blocked by antiestrogen and ovariectomy, indicating that the induced proliferation is mediated by ERalpha signaling and requires estrogen stimulation. These data indicate the chaperone activity of SNCG on stimulation of steroid receptor signaling in mammary gland and, thus induces extensive mammary gland proliferation and contributes to the hormonal impact on mammary tumorigenesis.
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Affiliation(s)
- Y E Liu
- Department of Radiation Oncology, Long Island Jewish Medical Center, Albert Einstein College of Medicine, The Feinstein Institute for Medical Research, New Hyde Park, NY 11040, USA
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Surgucheva I, McMahon B, Surguchov A. gamma-synuclein has a dynamic intracellular localization. ACTA ACUST UNITED AC 2006; 63:447-58. [PMID: 16732559 DOI: 10.1002/cm.20135] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
gamma-Synuclein is a member of the synuclein family consisting of three proteins. Within the last several years increasing attention has focused on these proteins because of their role in human diseases. alpha-Synuclein relevance to Parkinson's disease is based on mutations found in familial cases of the disease and its presence in filaments and inclusion bodies in sporadic cases. gamma-Synuclein is implicated in some forms of cancer and ocular diseases, while beta-synuclein may antagonize their pathological functions. In this paper we present data on the localization and properties of gamma-synuclein in several neuronal and nonneuronal cell cultures. We show that contrary to the current opinion, gamma-synuclein is not an exclusively cytoplasmic protein, but has a dynamic localization and can associate with subcellular structures. It is present in the perinuclear area and may be associated to centrosomes. On late steps of mitosis gamma-synuclein is not found in the centrosomes, and redistributes to the midbody in telophase. Under stress conditions a translocation of gamma-synuclein from the perinuclear area to the nucleus occurs exhibiting nucleocytoplasmic shuttling. gamma-Synuclein overexpression reduces neurite outgrowth in a greater extent then alpha-synuclein overexpression. These data support the view that gamma-synuclein may change its intracellular localization and associate with subcellular structures in response to intracellular signaling or stress.
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Affiliation(s)
- Irina Surgucheva
- Retinal Biology Research Laboratory, Veterans Administration Medical Center, Kansas City, MO 66148, USA.
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42
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Wu K, Quan Z, Weng Z, Li F, Zhang Y, Yao X, Chen Y, Budman D, Goldberg ID, Shi YE. Expression of neuronal protein synuclein gamma gene as a novel marker for breast cancer prognosis. Breast Cancer Res Treat 2006; 101:259-67. [PMID: 16821081 DOI: 10.1007/s10549-006-9296-7] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2006] [Accepted: 05/31/2006] [Indexed: 12/24/2022]
Abstract
Synucleins are emerging as central players in the fundamental neural processes and in the formation of pathologically insoluble deposits characteristic of neurodegenerative diseases. However, synuclein gamma (SNCG), previously identified as a breast cancer specific gene (BCSG1), is also highly expressed in breast carcinomas, but not expressed in normal or benign breast tissues. We analyzed SNCG gene expression in 93 clinical breast specimens and associated it with clinical outcome. Overall SNCG mRNA expression was detectable in 36% breast cancers. However, 81% of stage III/IV breast cancers were positive for SNCG expression, while only 15% of stage I/II breast cancers were positive for SNCG expression. In contrast, SNCG was undetectable in benign breast lesions. Expression of SNCG in the primary tumor also significantly associated with lymph node involvement and metastasis. There was no significant correlation between SNCG gene expression and age, menstruation, and status of ER, PR, PCNA, and HER-2. Patients whose tumors expressed SNCG had a significantly shorter DFS and a high probability of death when compared with those whose tumors did not express SNCG. The hazard ratio of metastasis or recurrence according to the SNCG status was 4.515 (95% CI, 1,188-17.154; P = 0.027). Cox multivariate analysis showed that SNCG had independent prognostic significance above and beyond conventional variables. This study suggests that the expression of SNCG is an independent predictive marker for recurrence and metastasis in breast cancer progression. SNCG is expected to be a useful marker for breast cancer progression and a potential target for breast cancer treatment.
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Affiliation(s)
- Kejin Wu
- Department of General Surgery, XinHua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China
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43
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Amer DAM, Irvine GB, El-Agnaf OMA. Inhibitors of alpha-synuclein oligomerization and toxicity: a future therapeutic strategy for Parkinson's disease and related disorders. Exp Brain Res 2006; 173:223-33. [PMID: 16733698 DOI: 10.1007/s00221-006-0539-y] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2006] [Accepted: 05/01/2006] [Indexed: 01/12/2023]
Abstract
An abundance of genetic, histopathological, and biochemical evidence has implicated the neuronal protein, alpha-synuclein (alpha-syn) as a key player in the development of several neurodegenerative diseases, the so-called synucleinopathies, of which Parkinson's disease (PD) is the most prevalent. Development of disease appears to be linked to events that increase the intracellular concentration of alpha-syn or cause its chemical modification, either of which can accelerate the rate at which it forms aggregates. Examples of such events include increased copy number of genes, decreased rate of degradation via the proteasome or other proteases, or altered forms of alpha-syn, such as truncations, missense mutations, or chemical modifications by oxidative reactions. Aggregated forms of the protein, especially newly formed soluble aggregates, are toxic to cells, so that one therapeutic strategy would be to reduce the rate at which such oligomerization occurs. We have therefore designed several peptides and also identified small molecules that can inhibit alpha-syn oligomerization and toxicity in vitro. These compounds could serve as lead compounds for the design of new drugs for the treatment of PD and related disorders in the future.
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Affiliation(s)
- Dena A M Amer
- Department of Biochemistry, Faculty of Medicine and Health Sciences, United Arab Emirates University, P.O.Box: 17666, Al Ain, United Arab Emirates
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44
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Inaba S, Li C, Shi YE, Song DQ, Jiang JD, Liu J. Synuclein gamma inhibits the mitotic checkpoint function and promotes chromosomal instability of breast cancer cells. Breast Cancer Res Treat 2006; 94:25-35. [PMID: 16142440 DOI: 10.1007/s10549-005-6938-0] [Citation(s) in RCA: 63] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
Aberrant expressions of the neuronal protein synuclein gamma (SNCG) in malignant mammary epithelial cells are strongly associated with the progression of breast cancer. SNCG is not expressed in normal breast tissues but abundantly expressed in a high percentage of invasive and metastatic breast carcinomas. Several studies have demonstrated that SNCG expression significantly stimulates proliferation, invasion, and metastasis of breast cancer cells. To elucidate the molecular and cellular mechanisms underlying the tumorigenic functions of SNCG, we investigated the effects of SNCG expression on the mitotic checkpoint function of breast cancer cells. By conducting several different lines of investigations, we now demonstrate that SNCG expression in breast cancer cells overrides the mitotic checkpoint control and confers the cellular resistance to anti-microtubule drug-caused apoptosis. We further show that the inhibitory effects of SNCG on mitotic checkpoint can be overthrown by enforced overexpression of the mitotic checkpoint protein BubR1 in SNCG-expressing cells. These new findings combined with our previous observation that SNCG intracellularly associates with BubR1 together suggest that SNCG expression compromises the mitotic checkpoint control by inhibition of the normal function of BubR1, thereby promoting genetic instability. Genetic instability is recognized as an important contributing factor in tumorigenesis. Hence, our studies gain insight into the mechanisms whereby SNCG expression advances breast cancer disease progression and fasters tumor metastasis.
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Affiliation(s)
- Satoru Inaba
- VA Palo Alto Health Care System, Palo Alto, CA 94304, USA
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45
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Tamura G. Alterations of tumor suppressor and tumor-related genes in the development and progression of gastric cancer. World J Gastroenterol 2006; 12:192-8. [PMID: 16482617 PMCID: PMC4066026 DOI: 10.3748/wjg.v12.i2.192] [Citation(s) in RCA: 160] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The development and progression of gastric cancer involves a number of genetic and epigenetic alterations of tumor suppressor and tumor-related genes. The majority of differentiated carcinomas arise from intestinal metaplastic mucosa and exhibit structurally altered tumor suppressor genes, typified by p53, which is inactivated via the classic two-hit mechanism, i.e. loss of heterozygosity (LOH) and mutation of the remaining allele. LOH at certain chromosomal loci accumulates during tumor progression. Approximately 20% of differentiated carcinomas show evidence of mutator pathway tumorigenesis due to hMLH1 inactivation via hypermethylation of promoter CpG islands, and exhibit high-frequency microsatellite instability. In contrast, undifferentiated carcinomas rarely exhibit structurally altered tumor suppressor genes. For instance, while methylation of E-cadherin is often observed in undifferentiated carcinomas, mutation of this gene is generally associated with the progression from differentiated to undifferentiated carcinomas. Hypermethylation of tumor suppressor and tumor-related genes, including APC, CHFR, DAP-kinase, DCC, E-cadherin, GSTP1, hMLH1, p16, PTEN, RASSF1A, RUNX3, and TSLC1, can be detected in both differentiated and undifferentiated carcinomas at varying frequencies. However, the significance of the hypermethylation varies according to the analyzed genomic region, and hypermethylation of these genes can also be present in non-neoplastic gastric epithelia. Promoter demethylation of specific genes, such as MAGE and synuclein γ, can occur during the progressive stages of both histological types, and is associated with patient prognosis. Thus, while the molecular pathways of gastric carcinogenesis are dependent on histological background, specific genetic alterations can still be used for risk assessment, diagnosis, and prognosis.
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Affiliation(s)
- Gen Tamura
- Department of Pathology, Yamagata University School of Medicine, 2-2-2 Iida-nishi, Yamagata 990-9585, Japan.
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Liu H, Liu W, Wu Y, Zhou Y, Xue R, Luo C, Wang L, Zhao W, Jiang JD, Liu J. Loss of epigenetic control of synuclein-gamma gene as a molecular indicator of metastasis in a wide range of human cancers. Cancer Res 2005; 65:7635-43. [PMID: 16140929 DOI: 10.1158/0008-5472.can-05-1089] [Citation(s) in RCA: 106] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Metastasis is a major contributing factor to poor prognosis in cancer. Reliable and sensitive biomarkers that indicate the development of metastasis of primary tumors would be of great clinical use. In this study, we show that the neuronal protein synuclein-gamma (SNCG) is abnormally expressed in a high percentage (67.5%) of tumor tissues of diversified cancer types, including liver, esophagus, colon, gastric, lung, prostate, cervical, and breast cancer, but rarely expressed in tumor-matched nonneoplastic adjacent tissues (0.6%). Expressions of SNCG protein in different cancer types all display stage-specific patterns of very low expression in stage I and high expression in stages II to IV. Importantly, we observe a strong association between SNCG protein expression in primary tumors with distant metastasis in patients regardless of the cancer type (60.6%, P < 0.001). By performing genomic sequencing and methylation-specific PCR assays, we identify an inclusive demethylation of CpG sites within the CpG island of SNCG gene in every tumor sample (100%) across all cancer types, illustrating a universal loss of the epigenetic control of SNCG gene expression in tumors and further demonstrating that the demethylation of SNCG CpG island is primarily responsible for the aberrant expression of SNCG protein in cancerous tissues. These new findings strongly suggest that reactivation of SNCG gene expression by DNA demethylation is a common critical contributing factor to malignant progression of many solid tumors and its expression in primary carcinomas is an effective molecular indicator of distant metastasis. Our studies also suggest that the methylation status of SNCG gene can be used as a sensitive molecular tool in early detections of tumorigenesis.
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Affiliation(s)
- Haiyan Liu
- Research Service, Department of Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304, USA
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Subramanian S, West RB, Marinelli RJ, Nielsen TO, Rubin BP, Goldblum JR, Patel RM, Zhu S, Montgomery K, Ng TL, Corless CL, Heinrich MC, van de Rijn M. The gene expression profile of extraskeletal myxoid chondrosarcoma. J Pathol 2005; 206:433-44. [PMID: 15920699 DOI: 10.1002/path.1792] [Citation(s) in RCA: 56] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Extraskeletal myxoid chondrosarcoma (EMC) is a soft tissue tumour that occurs primarily in the extremities and is characterized by a balanced translocation most commonly involving t(9;22) (q22;q12). The morphological spectrum of EMC is broad and thus a diagnosis based on histology alone can be difficult. Currently, no systemic therapy exists that improves survival in patients with EMC. In the present study, gene expression profiling has been performed to discover new diagnostic markers and potential therapeutic targets for this tumour type. Global gene expression profiling of ten EMCs and 26 other sarcomas using 42,000 spot cDNA microarrays revealed that the cases of EMC were closely related to each other and distinct from the other tumours profiled. Significance analysis of microarrays (SAM) identified 86 genes that distinguished EMC from the other sarcomas with 0.25% likelihood of false significance. NMB, DKK1, DNER, CLCN3, and DEF6 were the top five genes in this analysis. In situ hybridization for NMB gene expression on tissue microarrays (TMAs) containing a total of 1164 specimens representing 62 different sarcoma types and 15 different carcinoma types showed that NMB was highly expressed in 17 of 22 EMC cases and very rarely expressed in other tumours and thus could function as a novel diagnostic marker. High levels of expression of PPARG and the gene encoding its interacting protein, PPARGC1A, in most EMCs suggest activation of lipid metabolism pathways in this tumour. Small molecule inhibitors for PPARG exist and PPARG could be a potential therapeutic target for EMC.
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Affiliation(s)
- Subbaya Subramanian
- Department of Pathology, Stanford University Medical Center, Stanford, CA 94035, USA
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Snyder H, Wolozin B. Pathological proteins in Parkinson's disease: focus on the proteasome. J Mol Neurosci 2005; 24:425-42. [PMID: 15655264 DOI: 10.1385/jmn:24:3:425] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2004] [Accepted: 04/11/2004] [Indexed: 12/21/2022]
Abstract
Parkinson's disease (PD) is a multifactorial disease that appears to arise from the effects of both genetic and environmental influences. Pesticides and heavy metals are the principle environmental factors that appear to impact on PD. The known genetic factors include multiple genes that have been identified in related parkinsonian syndromes, as well as alpha-synuclein. Genes associated with either PD or Parkinson-related disorders include parkin, DJ-1, ubiquitin C-terminal hydrolase isozyme L1 (UCH-L1), nuclear receptor-related factor 1, and alpha-synuclein. Alpha-synuclein is particularly notable because it aggregates readily and is the main component of Lewy bodies (LBs). Aggregated alpha-synuclein binds the proteasome and potently inhibits proteasomal activity. Because ubiquitin accumulates in LBs, and parkin and UCH-L1 also interact with the ubiquitin proteasomal system, proteasomal dysfunction is thought to contribute to the pathophysiology of PD. Increasing numbers of experiments suggest that neurotoxins might interact with alpha-synuclein or other Parkinson-related proteins to contribute to the pathophysiology of PD. Transgenic animal models overexpressing alpha-synuclein develop age-dependent motor dysfunction and inclusions in the brain stem that contain alpha-synuclein. These models are very helpful in elucidating the pathophysiology of PD but do not completely recapitulate the disease process. The relationship between these transgenic models and PD is a subject of intense investigation.
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Affiliation(s)
- Heather Snyder
- Boston University School of Medicine, 715 ALbany Street, Room L-603, Boston, MA 02118-2526, USA
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Badano JL, Teslovich TM, Katsanis N. The centrosome in human genetic disease. Nat Rev Genet 2005; 6:194-205. [PMID: 15738963 DOI: 10.1038/nrg1557] [Citation(s) in RCA: 182] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
The centrosome is an indispensable component of the cell-cycle machinery of eukaryotic cells, and the perturbation of core centrosomal or centrosome-associated proteins is linked to cell-cycle misregulation and cancer. Recent work has expanded our understanding of the functional complexity and importance of this organelle. The centrosomal localization of proteins that are involved in human genetic disease, and the identification of novel centrosome-associated proteins, has shown that numerous, seemingly unrelated, cellular processes can be perturbed by centrosomal dysfunction. Here, we review the mechanistic relationship between human disease phenotypes and the function of the centrosome, and describe some of the newly-appreciated functions of this organelle in animal cells.
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Affiliation(s)
- Jose L Badano
- McKusick-Nathans Institute of Genetic Medicine, John Hopkins University, 533 Broadway Research Building, 733 N. Broadway, Baltimore, Maryland 21205, USA
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Snyder H, Mensah K, Hsu C, Hashimoto M, Surgucheva IG, Festoff B, Surguchov A, Masliah E, Matouschek A, Wolozin B. β-Synuclein Reduces Proteasomal Inhibition by α-Synuclein but Not γ-Synuclein. J Biol Chem 2005; 280:7562-9. [PMID: 15591046 DOI: 10.1074/jbc.m412887200] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
The accumulation of aggregated alpha-synuclein is thought to contribute to the pathogenesis of Parkinson's disease. Recent studies indicate that aggregated alpha-synuclein binds to S6', a component of the 19 S subunit in the 26 S proteasome and inhibits 26 S proteasomal degradation, both ubiquitin-independent and ubiquitin-dependent. The IC(50) of aggregated alpha-synuclein for inhibition of the 26 S ubiquitin-independent proteasomal activity is approximately 1 nm. alpha-Synuclein has two close homologues, termed beta-synuclein and gamma-synuclein. In the present study we compared the effects of the three synuclein homologues on proteasomal activity. The proteasome exists as a 26 S and a 20 S species, with the 26 S proteasome containing the 20 S core and 19 S cap. Monomeric alpha- and beta-synucleins inhibited the 20 S and 26 S proteasomal activities only weakly, but monomeric gamma-synuclein strongly inhibited ubiquitin-independent proteolysis. The IC(50) of monomeric gamma-synuclein for the 20 S proteolysis was 400 nm. In monomeric form, none of the three synuclein proteins inhibited 26 S ubiquitin-dependent proteasomal activity. Although beta-synuclein had no direct effect on proteasomal activity, co-incubating monomeric beta-synuclein with aggregated alpha-synuclein antagonized the inhibition of the 26 S ubiquitin-independent proteasome by aggregated alpha-synuclein when added before the aggregated alpha-synuclein. Co-incubating beta-synuclein with gamma-synuclein had no effect on the inhibition of the 20 S proteasome by monomeric gamma-synuclein. Immunoprecipitation and pull-down experiments suggested that antagonism by beta-synuclein resulted from binding to alpha-synuclein rather than binding to S6'. Pull-down experiments demonstrated that recombinant monomeric beta-synuclein does not interact with the proteasomal subunit S6', unlike alpha-synuclein, but beta-synuclein does bind alpha-synuclein and competes with S6' for binding to alpha-synuclein. Based on these data, we hypothesize that the alpha- and gamma-synucleins regulate proteasomal function and that beta-synuclein acts as a negative regulator of alpha-synuclein.
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Affiliation(s)
- Heather Snyder
- Department of Pharmacology, Loyola University Medical Center, Maywood, Illinois 60153, USA
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