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Post by skyship on Mar 29, 2010 18:57:58 GMT -5
Well then! Rotenone Induces Apoptosis via Activation of Bad in Human Dopaminergic SH-SY5Y Cells"In rotenone-induced cell death, rotenone induced Bad dephosphorylation without changing the amount of Bad proteins. Rotenone also increased the amount of α-synuclein in cells showing morphological changes in response to rotenone. Because Bad and α-synuclein are known to bind to 14-3-3 proteins, we examined the effects of rotenone on these complexes. Whereas a decreased Bad amount bound to 14-3-3 proteins, rotenone increased α-synuclein binding to these proteins. Beccause dephosphorylation by calcineurin activates Bad, we examined the possible involvement of Bad activation in rotenone-induced apoptosis by using the calcineurin inhibitor tacrolimus (FK506). Tacrolimus suppressed two rotenone-induced actions: Bad dephosphorylation and apoptosis. Furthermore, the inhibition of caspase-9, which functions downstream from Bad, completely suppressed rotenone-induced apoptosis. Our findings demonstrate that Bad activation plays a role in rotenone-induced apoptosis of SH-SY5Y cells. Previous SectionNext Section Parkinson's disease is characterized by selective nigrostriatal dopaminergic degeneration and the formation of ubiquitin- and α-synuclein-positive cytoplasmic inclusions known as Lewy bodies (Spillantini et al., 1997). The etiology of the nigral dopamine neuron degeneration is unknown, although both genetic mutations and environmental factors have been identified as contributing to certain forms of this disorder (Shastry, 2001). An established hallmark of Parkinson's disease is a reduction in the activity of brain mitochondrial enzyme complex I (Schapira et al., 1990).".......... jpet.aspetjournals.org/content/311/3/948.fullBad and α-synucleinn are known to bind to 14-3-3 proteinsa synuclein positive cytoplasmic inclusions known as Lewy bodies. Human Dopaminergic SH-SY5Y CellsBad: &a-synuclein
14-3-3 proteins
Lewy bodies
some terms! skyship
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Post by skyship on Mar 29, 2010 19:33:32 GMT -5
#945 synuclein? ? or alpha synuclein? (alpha)SYNUCLEIN ACCUMULATION IN SKIN NERVE FIBERS REVEALED BY SKIN BIOPSY IN PURE AUTONOMIC FAILURE T. Shishido, M. Ikemura, T. Obi, K. Yamazaki, T. Terada, A. Sugiura, Y. Saito, S. Murayama, and K. Mizoguchi www.neurology.org/cgi/content/citation/74/7/608============================== alpha synuclein Green Flour Protein GFP www.jyi.org/articleimages/1350/originals/img0.jpg========================== alpha or #945 synuclein -Synuclein Promotes Mitochondrial Deficit and Oxidative Stress Abnormal accumulation of the presynaptic protein {alpha}-synuclein has recently been implicated in the pathogenesis of Alzheimer’s and Parkinson’s diseases. Because neurodegeneration in these conditions might be associated with mitochondrial dysfunction and oxidative stress, the effects of {alpha}-synuclein were investigated in a hypothalamic neuronal cell line (GT1-7). {alpha}-Synuclein overexpression in these cells resulted in formation of {alpha}-synuclein-immunopositive inclusion-like structures and mitochondrial alterations accompanied by increased levels of free radicals and decreased secretion of gonadotropin-releasing hormone. These alterations were ameliorated by pretreatment with anti-oxidants such as vitamin E. Taken together these results suggest that abnormal accumulation of {alpha}-synuclein could lead to mitochondrial alterations that may result in oxidative stress and, eventually, cell death. could fibers be ++++++++++++++++ Abnormal accumulation of the presynaptic protein {alpha}-synuclein alpha synuclein: The amyloid precursor protein: en.wikipedia.org/wiki/Alpha-synucleinyeppppppppppppppppp alpha sin nu kle on synuclein beginning nucleolus:................ ============================ Alpha-synuclein and the Lewy body disorders. Department of Pathology, Mayo Clinic, Jacksonville, Florida 32224, USA. ickson.dennis@mayo.edu alpha-Synuclein has risen to prominence during the past 5 years because of its association with several neurodegenerative diseases that have come to be known as the synucleinopathies. The clinical phenotype of the synucleinopathies is variable, with the most common being parkinsonism, autonomic dysfunction, and dementia. Progress has been made in clinical, neuropathologic and biochemical characterization of the synucleinopathies and their differentiation from other neurodegenerative disorders. At the molecular level, the synucleinopathies have conformational and post-translational modifications of synuclein that favor its fibrillization and aggregation in inclusions in neurons and glia. Whether inclusion body formation is an adaptive response or is directly related to degeneration of neuronal and glial cells is a topic of current research. www.ncbi.nlm.nih.gov/pubmed/11470957skyship
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Post by skyship on Mar 29, 2010 19:48:02 GMT -5
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Post by skyship on Mar 29, 2010 19:55:15 GMT -5
Abstract Recently, -synuclein was shown to be a structural component of the filaments in Lewy bodies (LBs) of Parkinson's disease (PD), dementia with LBs (DLB) as well as the LB variant of Alzheimer's disease, and this suggests that -synuclein could play a mechanistic role in the pathogenesis of these disorders. To determine whether -synuclein is a building block of inclusions in other neurodegenerative movement disorders, we examined brains from patients with multiple system atrophy (MSA) and detected -synuclein, but not - or -synuclein, in glial cytoplasmic inclusions (GCIs) throughout the MSA brain. In MSA white matter, -synuclein-positive GCIs were restricted to oligodendrocytes, and -synuclein accumulated selectively in MSA white matter with -synuclein-positive GCIs. Taken together with evidence that LBs contain insoluble -synuclein, our data suggest that a reduction in the solubility of -synuclein may induce this protein to form filaments that aggregate into cytoplasmic inclusions, which contribute to the dysfunction or death of glial cells as well as neurons in neurodegenerative disorders with different phenotypes. www3.interscience.wiley.com/journal/109681909/abstract?CRETRY=1&SRETRY=0skyship
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Post by skyship on Mar 29, 2010 20:04:17 GMT -5
Bad proteins: -Synuclein Shares Physical and Functional Homology with 14-3-3 Proteins -Synuclein has been implicated in the pathophysiology of many neurodegenerative diseases, including Parkinson's disease (PD) and Alzheimer's disease. Mutations in alpha -synuclein cause some cases of familial PD (Polymeropoulos et al., 1997; Kruger et al., 1998). In addition, many neurodegenerative diseases show accumulation of alpha -synuclein in dystrophic neurites and in Lewy bodies (Spillantini et al., 1998). Here, we show that alpha -synuclein shares physical and functional homology with 14-3-3 proteins, which are a family of ubiquitous cytoplasmic chaperones. Regions of alpha -synuclein and 14-3-3 proteins share over 40% homology. In addition, alpha -synuclein binds to 14-3-3 proteins, as well as some proteins known to associate with 14-3-3, including protein kinase C, BAD, and extracellular regulated kinase, but not Raf-1. We also show that overexpression of alpha -synuclein inhibits protein kinase C activity. The association of alpha -synuclein with BAD and inhibition of protein kinase C suggests that increased expression of alpha -synuclein could be harmful. Consistent with this hypothesis, we observed that overexpression of wild-type alpha -synuclein is toxic, and overexpression of alpha -synuclein containing the A53T or A30P mutations exhibits even greater toxicity. The activity and binding profile of alpha -synuclein suggests that it might act as a protein chaperone and that accumulation of alpha -synuclein could contribute to cell death in neurodegenerative diseases. Key words: 14-3-3 proteins; Alzheimer's disease; apoptosis; BAD; extracellular regulated kinase; Parkinson's disease; protein kinase C; synuclein www.jneurosci.org/cgi/content/short/19/14/5782================== the many faces of a protein. Unfolded alpha-synuclein (top) converts to an apparently spherical form, which may accumulate in the cytoplasm. As concentrations increase, spheres may join together to form potentially toxic chainlike protofibrils (bottom center). Chains can either fuse head-to-tail to produce annular protofibrils (bottom left) or side-to-side to produce the large fibrils that compose Lewy bodies (bottom right). focus.hms.harvard.edu/2001/Nov9_2001/neurology.htmlskyship
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Post by skyship on Mar 29, 2010 23:14:32 GMT -5
14.3.3 proteins: Detection of 14-3-3 protein in the cerebrospinal fluid supports the diagnosis of Creutzfeldt-Jakob disease. Zerr I, Bodemer M, Gefeller O, Otto M, Poser S, Wiltfang J, Windl O, Kretzschmar HA, Weber T. Neurologische Klinik und Poliklinik, Georg-August-Universität, Göttingen, Germany. Comment in: * Ann Neurol. 2000 May;47(5):683-4. The analysis of 14-3-3 protein in cerebrospinal fluid (CSF) was shown to be highly sensitive and specific for the diagnosis of Creutzfeldt-Jakob disease (CJD). However, the predictive value of this test in the clinical diagnosis of, and its relation to, sporadic, genetic, and iatrogenic CJD cases have yet to be established. CSF samples of suspect CJD cases seen in the prospective German surveillance study were tested for the presence of 14-3-3 protein by using a modified western blot (WB) technique. WB detected 14-3-3 protein in 95.4% of definite and 92.8% of probable cases. In two patients classified initially as not having CJD the test was positive, and both were later proved to have definite CJD. The positive predictive value is 94.7% and the negative predictive value is 92.4%. False-positive results in a single CSF analysis were seen in patients with herpes simplex encephalitis, hypoxic brain damage, atypical encephalitis, intracerebral metastases of a bronchial carcinoma, metabolic encephalopathy, and progressive dementia of unknown cause. WB analysis for 14-3-3 protein was positive in only 5 of 10 cases of familial forms of spongiform encephalopathies. CSF analysis for 14-3-3 protein should thus be performed in any case suspect for CJD. www.ncbi.nlm.nih.gov/pubmed/9450766skyship
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