Organization, expression and polymorphism of the human persyn gene

Ninkina, Natalia; Alimova-Kost, Maria V.; Paterson, James W. E.; Delaney, Liz; Cohen, Brian; Imreh, Stefan; Гнучев, Н. В.; Davies, Alun M.; Buchman, Vladimir L.

doi:10.1093/hmg/7.9.1417

Cited by 97 publications

(75 citation statements)

References 34 publications

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“…Sncg (also known as Persyn) is a small protein expressed in subsets of neurons and in carcinogenic breast and ovarian tissue believed to perform chaperone-like functions Ninkina et al, 1998;Bruening et al, 2000;Surguchov et al, 2001;George, 2002;Surgucheva et al, 2005). In the mouse retina, during development Sncg is regulated by the transcription factor Brn3b and expressed specifically in RGCs (Mu et al, 2004), and in the adult remains expressed in RGCs and not other retina cell types (Trimarchi et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Retinal Ganglion Cells Downregulate Gene Expression and Lose Their Axons within the Optic Nerve Head in a Mouse Glaucoma Model

Soto¹,

Oglesby²,

Buckingham³

et al. 2008

J. Neurosci.

258

236

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Little is known about molecular changes occurring within retinal ganglion cells (RGCs) before their death in glaucoma. Taking advantage of the fact that ␥-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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Section: Discussionmentioning

confidence: 99%

Retinal Ganglion Cells Downregulate Gene Expression and Lose Their Axons within the Optic Nerve Head in a Mouse Glaucoma Model

Soto¹,

Oglesby²,

Buckingham³

et al. 2008

J. Neurosci.

258

236

View full text Add to dashboard Cite

show abstract

“…Extraction of RNA from mouse tissues, Northern blotting, and preparation of labeled probes were carried out as described previously (7,36).…”

Section: Methodsmentioning

confidence: 99%

Neurons Expressing the Highest Levels of γ-Synuclein Are Unaffected by Targeted Inactivation of the Gene

Ninkina

Papachroni

Robertson

et al. 2003

Molecular and Cellular Biology

104

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Homologous recombination in ES cells was employed to generate mice with targeted deletion of the first three exons of the ␥-synuclein gene. Complete inactivation of gene expression in null mutant mice was confirmed on the mRNA and protein levels. Null mutant mice are viable, are fertile, and do not display evident phenotypical abnormalities. The effects of ␥-synuclein deficiency on motor and peripheral sensory neurons were studied by various methods in vivo and in vitro. These two types of neurons were selected because they both express high levels of ␥-synuclein from the early stages of mouse embryonic development but later in the development they display different patterns of intracellular compartmentalization of the protein. We found no difference in the number of neurons between wild-type and null mutant animals in several brain stem motor nuclei, in lumbar dorsal root ganglia, and in the trigeminal ganglion. The survival of ␥-synuclein-deficient trigeminal neurons in various culture conditions was not different from that of wild-type neurons. There was no difference in the numbers of myelinated and nonmyelinated fibers in the saphenous nerves of these animals, and sensory reflex thresholds were also intact in ␥-synuclein null mutant mice. Nerve injury led to similar changes in sensory function in wild-type and mutant mice. Taken together, our data suggest that like ␣-synuclein, ␥-synuclein is dispensable for the development and function of the nervous system. Several neurodegenerative diseases have been recently coalesced into a distinct group named synucleinopathies (12,16,20,53). Although they are diverse in symptoms and clinical signs, these diseases share a common histopathological feature, i.e., formation of large intracellular inclusions whose principal component is an aggregated small protein, ␣-synuclein. Neither the normal cellular function of ␣-synuclein nor the exact mechanism of its involvement in neurodegeneration is clearly understood; possible scenarios are discussed in many recent reviews (see, for example, references 10, 28, 33, 34, and 43). Even less clear are the normal functions and roles in neurodegeneration of the other two members of the synuclein family. Both ␤-synuclein/PNP14 (24, 35) and ␥-synuclein/BCSG1/persyn (7, 26, 29) have a very high degree of amino acid similarity with ␣-synuclein within the N-terminal KTK repeat region of the protein molecule, and this is reflected in such common features of synucleins as a native unfolded state in physiological solutions, reversible binding to lipid vesicles, and localization in presynaptic terminals (13,25,31). However, the C-terminal regions of synucleins, although all highly acidic, are rather different (7, 29, 52). It is perhaps this structural diversity that leads to differences in the behavior of synucleins in vitro and in various in vivo model systems. Consistent with the finding that ␤-synuclein and ␥-synuclein are much less fibrillogenic than ␣-synuclein (4, 47, 55), aggregates of these two proteins are not constituents of Lewy b...

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“…When overexpressed, SNCG stimulates proliferation and induces metastasis of breast cancer cells (22)(23)(24)(25)(26). Analysis of breast tumor samples did not identify any sequence variation of SNCG gene from its original normal neuronal environment and no gene amplification was detected either (27), suggesting that transcriptional activation could account for its abundant expression in breast cancer cells. By analyzing the promoter region of SNCG gene and conducting genomic sequencing, we had shown that the loss of methylation control in a CpG island located in exon 1 of SNCG was primarily responsible for the aberrant expression of this neuronal protein in breast carcinoma (28) and in some ovarian carcinomas (29).…”

Section: Introductionmentioning

confidence: 99%

Loss of Epigenetic Control of Synuclein-γ Gene as a Molecular Indicator of Metastasis in a Wide Range of Human Cancers

Liu

Liu²,

Wu³

et al. 2005

Cancer Research

132

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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-; (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 tumormatched nonneoplastic adjacent tissues (0.6%). Expressions of SNCG protein in different cancer types all display stagespecific 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. (Cancer Res 2005; 65(17): 7635-43)

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Organization, expression and polymorphism of the human persyn gene

Cited by 97 publications

References 34 publications

Retinal Ganglion Cells Downregulate Gene Expression and Lose Their Axons within the Optic Nerve Head in a Mouse Glaucoma Model

Retinal Ganglion Cells Downregulate Gene Expression and Lose Their Axons within the Optic Nerve Head in a Mouse Glaucoma Model

Neurons Expressing the Highest Levels of γ-Synuclein Are Unaffected by Targeted Inactivation of the Gene

Loss of Epigenetic Control of Synuclein-γ Gene as a Molecular Indicator of Metastasis in a Wide Range of Human Cancers

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