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10.1073/pnas.1618627114 http://scihub22266oqcxt.onion/10.1073/pnas.1618627114 C5293033!5293033 !28096359     free     free     free Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 267.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 267.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Warning: imagejpeg(C:\Inetpub\vhosts\kidney.de\httpdocs\phplern\28096359 .jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117       Proc+Natl+Acad+Sci+U+S+A 2017 ; 114 (5 ): 1183-1188 Nephropedia Template TP {{tp|p=28096359 |t=2017. ?-Synuclein binds and sequesters PIKE-L into Lewy bodies, triggering dopaminergic cell death via AMPK hyperactivation |pdf=|usr=}}{{28096359 }} gab.com Text -Synuclein binds and sequesters PIKE-L into Lewy bodies, triggering dopaminergic cell death via AMPK hyperactivation JO: Proc Natl Acad Sci U S A http://www.kidney.de/pget.php?&tw=1&pmid=28096359 #FOAvip The abnormal aggregation of fibrillar ?-synuclein in Lewy bodies plays a critical role in the pathogenesis of Parkinson's disease. However, the molecular mechanisms regulating ?-synuclein pathological effects are incompletely understood. Here we show that ?-synuclein binds phosphoinositide-3 kinase enhancer L (PIKE-L) in a phosphorylation-dependent manner and sequesters it in Lewy bodies, leading to dopaminergic cell death via AMP-activated protein kinase (AMPK) hyperactivation. ?-Synuclein interacts with PIKE-L, an AMPK inhibitory binding partner, and this action is increased by S129 phosphorylation through AMPK and is decreased by Y125 phosphorylation via Src family kinase Fyn. A pleckstrin homology (PH) domain in PIKE-L directly binds ?-synuclein and antagonizes its aggregation. Accordingly, PIKE-L overexpression decreases dopaminergic cell death elicited by 1-methyl-4-phenylpyridinium (MPP(+)), whereas PIKE-L knockdown elevates ?-synuclein oligomerization and cell death. The overexpression of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or ?-synuclein induces greater dopaminergic cell loss and more severe motor defects in PIKE-KO and Fyn-KO mice than in wild-type mice, and these effects are attenuated by the expression of dominant-negative AMPK. Hence, our findings demonstrate that ?-synuclein neutralizes PIKE-L's neuroprotective actions in synucleinopathies, triggering dopaminergic neuronal death by hyperactivating AMPK. Twit Text FOAVip -Synuclein binds and sequesters PIKE-L into Lewy bodies, triggering dopaminergic cell death via AMPK hyperactivation ????Proc Natl Acad Sci U S A http://www.kidney.de/pget.php?&tw=1&pmid=28096359 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=28096359 #FOAvip English Wikipedia <ref>{{Cite pmid|28096359 }}</ref> ?-Synuclein binds and sequesters PIKE-L into Lewy bodies, triggering dopaminergic cell death via AMPK hyperactivation #MMPMID28096359 Kang SS ; Zhang Z ; Liu X ; Manfredsson FP ; He L ; Iuvone PM ; Cao X ; Sun YE ; Jin L ; Ye K Proc Natl Acad Sci U S A 2017[Jan]; 114 (5 ): 1183-1188 PMID28096359 show ga The abnormal aggregation of fibrillar ?-synuclein in Lewy bodies plays a critical role in the pathogenesis of Parkinson's disease. However, the molecular mechanisms regulating ?-synuclein pathological effects are incompletely understood. Here we show that ?-synuclein binds phosphoinositide-3 kinase enhancer L (PIKE-L) in a phosphorylation-dependent manner and sequesters it in Lewy bodies, leading to dopaminergic cell death via AMP-activated protein kinase (AMPK) hyperactivation. ?-Synuclein interacts with PIKE-L, an AMPK inhibitory binding partner, and this action is increased by S129 phosphorylation through AMPK and is decreased by Y125 phosphorylation via Src family kinase Fyn. A pleckstrin homology (PH) domain in PIKE-L directly binds ?-synuclein and antagonizes its aggregation. Accordingly, PIKE-L overexpression decreases dopaminergic cell death elicited by 1-methyl-4-phenylpyridinium (MPP(+)), whereas PIKE-L knockdown elevates ?-synuclein oligomerization and cell death. The overexpression of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or ?-synuclein induces greater dopaminergic cell loss and more severe motor defects in PIKE-KO and Fyn-KO mice than in wild-type mice, and these effects are attenuated by the expression of dominant-negative AMPK. Hence, our findings demonstrate that ?-synuclein neutralizes PIKE-L's neuroprotective actions in synucleinopathies, triggering dopaminergic neuronal death by hyperactivating AMPK. |1-Methyl-4-phenylpyridinium/toxicity [MESH] |Adenylate Kinase/*metabolism [MESH] |Aged [MESH] |Aged, 80 and over [MESH] |Animals [MESH] |Cell Death [MESH] |Dopaminergic Neurons/*metabolism/ultrastructure [MESH] |Enzyme Activation [MESH] |GTP Phosphohydrolases/deficiency [MESH] |GTP-Binding Proteins/chemistry/*metabolism [MESH] |GTPase-Activating Proteins/chemistry/*metabolism [MESH] |Humans [MESH] |Lewy Bodies/*metabolism [MESH] |MPTP Poisoning/metabolism [MESH] |Mice [MESH] |Mice, Inbred C57BL [MESH] |Mice, Knockout [MESH] |Nerve Tissue Proteins/deficiency [MESH] |Phosphorylation [MESH] |Pleckstrin Homology Domains [MESH] |Protein Aggregation, Pathological [MESH] |Protein Binding [MESH] |Protein Interaction Mapping [MESH] |Protein Processing, Post-Translational [MESH] |Proto-Oncogene Proteins c-fyn/deficiency/metabolism [MESH]?-Synuclein binds and sequesters PIKE-L into Lewy bodies, triggering d(epmc).pdf DeepDyve Pubget Overpricing