Persyn, a Member of the Synuclein Family, Has a Distinct Pattern of Expression in the Developing Nervous System

Buchman, Vladimir L.; Hunter, Hamish J.A.; Piñón, Luzia G. P.; Thompson, Jane L.; Privalova, Eugenia M.; Ninkina, Natalia; Davies, Alun M.

doi:10.1523/jneurosci.18-22-09335.1998

Cited by 154 publications

(156 citation statements)

References 40 publications

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“…However, we have recently observed that the subcellular localization of ␥-synuclein in tumor cells may be altered. Previous studies have shown that ␥-synuclein is diffusely distributed in the cytoplasm of peripheral neurons, although it is also expressed in the brain (46). We have found in tumor cells, which over-express the wild-type ␥-synuclein, that the protein tends to accumulate in the nuclei.…”

Section: ␥-Synuclein In Cancer Cell Apoptosis and Drug Resistancementioning

confidence: 56%

γ-Synuclein Promotes Cancer Cell Survival and Inhibits Stress- and Chemotherapy Drug-induced Apoptosis by Modulating MAPK Pathways

Pan

Bruening

Giasson

et al. 2002

Journal of Biological Chemistry

117

105

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Synucleins are a family of highly conserved small proteins predominantly expressed in neurons. Recently we and others have found that ␥-synuclein is dramatically up-regulated in the vast majority of late-stage breast and ovarian cancers and that ␥-synuclein over-expression can enhance tumorigenicity. In the current study, we have found that ␥-synuclein is associated with two major mitogen-activated kinases (MAPKs), i.e. extracellular signal-regulated protein kinases (ERK1/2) and cJun N-terminal kinase 1 (JNK1), and have shown that over-expression of ␥-synuclein leads to constitutive activation of ERK1/2 and down-regulation of JNK1 in response to a host of environmental stress signals, including UV, arsenate, and heat shock. We also tested the effects of ␥-synuclein on apoptosis and activation of JNK and ERK in response to several chemotherapy drugs. We have found that ␥-synuclein-expressing cells are significantly more resistant to the chemotherapeutic drugs paclitaxel and vinblastine as compared with the parental cells. The resistance to paclitaxel can be partially obliterated when ERK activity is inhibited using a MEK1/2 inhibitor. Activation of JNK and its downstream caspase-3 by paclitaxel or vinblastine is significantly down-regulated in ␥-synuclein-expressing cells, indicating that the paclitaxel-or vinblastine-activated apoptosis pathway is blocked by ␥-synuclein. In contrast to paclitaxel and vinblastine, etoposide does not activate JNK, and ␥-synuclein over-expression has no apparent effect on this drug-induced apoptosis. Taken together, our data indicate that oncogenic activation of ␥-synuclein contributes to the development of breast and ovarian cancer by promoting tumor cell survival under adverse conditions and by providing resistance to certain chemotherapeutic drugs.Breast carcinoma is the second leading cause of cancer-related deaths in women of the Western world. In the United States alone over 180,000 new cases are diagnosed annually and more than 40,000 women die from this disease each year (1). Epithelial ovarian cancer continues to be the leading cause of death from gynecologic malignancies in the United States (1, 2). One woman in 70 in the U.S. will develop ovarian cancer in her lifetime, and one woman in 100 will die of this disease. Breast and ovarian cancer etiology are multifactorial, involving environmental factors, hormones, genetic susceptibility, and genetic changes during progression. Both cancers are a heterogeneous group of tumors with no unifying molecular alteration yet identified. A certain number of breast and ovarian cancer cases (ϳ5-10%) are attributed to inherited mutations in highly penetrant breast cancer susceptibility genes, such as BRCA1 and BRCA2 (reviewed in Ref. 3). However, the majority of the tumors occur in women with little or no family history, and the molecular basis of these sporadic cancers is still poorly defined.In an effort to identify other genes involved in the development and/or progression of breast and ovarian cancer, we and others used differentia...

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Section: ␥-Synuclein In Cancer Cell Apoptosis and Drug Resistancementioning

confidence: 56%

γ-Synuclein Promotes Cancer Cell Survival and Inhibits Stress- and Chemotherapy Drug-induced Apoptosis by Modulating MAPK Pathways

Pan

Bruening

Giasson

et al. 2002

Journal of Biological Chemistry

117

105

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“…Furthermore, the expression and intracellular localization of ␣-and ␤-syn are very similar in that both proteins are predominantly expressed in neurons of the central nervous system and are concentrated at the presynaptic terminal (19 -22). In contrast, ␥-syn is predominantly expressed in neurons of the peripheral nervous system, although it is also found at low levels in brain but diffusely distributed throughout the cytoplasm (23). Synoretin is similar to ␥-syn with respect to amino acid sequence and intracellular distribution, but synoretin is mainly expressed in the retina (17).…”

mentioning

confidence: 99%

A Hydrophobic Stretch of 12 Amino Acid Residues in the Middle of α-Synuclein Is Essential for Filament Assembly

Giasson¹,

Murray²,

Trojanowski

et al. 2001

Journal of Biological Chemistry

957

937

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Neuronal and oligodendrocytic aggregates of fibrillar ␣-synuclein define several diseases of the nervous system. It is likely that these inclusions impair vital metabolic processes and compromise vialibity of affected cells. Here, we report that a 12-amino acid stretch ( 71 VT-GVTAVAQKTV 82 ) in the middle of the hydrophobic domain of human ␣-synuclein is necessary and sufficient for its fibrillization based on the following observations: 1) human ␤-synuclein is highly homologous to ␣-synuclein but lacks these 12 residues, and it does not assemble into filaments in vitro; 2) the rate of ␣-synuclein polymerization in vitro decreases after the introduction of a single charged amino acid within these 12 residues, and a deletion within this region abrogates assembly; 3) this stretch of 12 amino acids appears to form the core of ␣-synuclein filaments, because it is resistant to proteolytic digestion in ␣-synuclein filaments; and 4) synthetic peptides corresponding to this 12-amino acid stretch self-polymerize to form filaments, and these peptides promote fibrillization of full-length human ␣-synuclein in vitro. Thus, we have identified key sequence elements necessary for the assembly of human ␣-synuclein into filaments, and these elements may be exploited as targets for the design of drugs that inhibit ␣-synuclein fibrillization and might arrest disease progression.

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“…tubulin) [55,101] and other amyloidogenic proteins (i.e. tau) [19,102]. Jensen et al [103] have hypothesized that an interaction between α-Syn and tau could link synaptic vesicles with microtubules.…”

Section: Phosphorylation At Serine129 Modulates α-Synuclein Protein-pmentioning

confidence: 99%

Modification of α-Synuclein by Phosphorylation: A Pivotal Event in the Cellular Pathogenesis of Parkinson’s Disease

Ganapathy¹

2017

Protein Phosphorylation

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Post-translational protein modifications play an important role in generating the large diversity of the proteome in comparison to the relatively small number of genes; phosphorylation being the most widespread. Phosphorylation of proteins regulates important molecularswitches for several cellular events and abnormal phosphorylation events are associated in many neurodegenerative diseases. In Parkinson's disease (PD) the main hallmark is the accumulation of cytoplasmic inclusions, Lewy bodies (LBs), consisting of α-synuclein (α-Syn) and ubiquitin. There's another key observation which is increasingly gaining prominence is a modified-form of α-Syn; the phospho α-Syn serine129 (pSyn). The significance of pSyn has gained importance in PD because its accumulation is distinctly enhanced in the diseased condition. The revelation of the involvement of pSyn on α-Syn aggregation, LB formation and neurotoxicity is crucial to understanding the pathogenesis and progression of PD. Since some in vitro and in vivo studies have indicated that pSyn is an early event preceding apoptosis, some important questions now needs to be explored in reference to the physiological functions regulated by phosphorylation, such as dopamine synthesis, vesicle mobilization, regulation of synaptic proteins, and synaptic plasticity. An investigation of the role of enzymes on the phosphorylation and clearance of α-Syn and region-specific susceptibility is required to be determined; to identify viable targets for new therapeutics.

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Persyn, a Member of the Synuclein Family, Has a Distinct Pattern of Expression in the Developing Nervous System

Cited by 154 publications

References 40 publications

γ-Synuclein Promotes Cancer Cell Survival and Inhibits Stress- and Chemotherapy Drug-induced Apoptosis by Modulating MAPK Pathways

γ-Synuclein Promotes Cancer Cell Survival and Inhibits Stress- and Chemotherapy Drug-induced Apoptosis by Modulating MAPK Pathways

A Hydrophobic Stretch of 12 Amino Acid Residues in the Middle of α-Synuclein Is Essential for Filament Assembly

Modification of α-Synuclein by Phosphorylation: A Pivotal Event in the Cellular Pathogenesis of Parkinson’s Disease

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