title: Radiation-Induced Alteration of the Brain Proteome: Understanding the Role of the Sirtuin 2 Deacetylase in a Murine Model.
abstract: Whole brain radiotherapy (WBRT) produces unwanted sequelae, albeit via unknown mechanisms. A deacetylase expressed in the central nervous system, Sirtuin 2 (SIRT2), has been linked to neurodegeneration. Therefore, we sought to challenge the notion that a single disease pathway is responsible for radiation-induced brain injury in Sirt2 wild-type (WT) and knockout (KO) mice at the proteomic level. We utilized isobaric tag for relative and absolute quantitation to analyze brain homogenates from Sirt2 WT and KO mice with and without WBRT. Selected proteins were independently verified, followed by ingenuity pathway analysis. Canonical pathways for Huntington's, Parkinson's, and Alzheimer's were acutely affected by radiation within 72 h of treatment. Although loss of Sirt2 preferentially affected both Huntington's and Parkinson's pathways, WBRT most significantly affected Huntington's-related proteins in the absence of Sirt2. Identical protein expression patterns were identified in Mog following WBRT in both Sirt2 WT and KO mice, revealing a proteomic radiation signature; however, long-term radiation effects were found to be associated with altered levels of a small number of key neurodegeneration-related proteins, identified as Mapt, Mog, Snap25, and Dnm1. Together, these data demonstrate the principle that the presence of Sirt2 can have significant effects on the brain proteome and its response to ionizing radiation.
authors.affiliation: Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institute of Health , 10 Center Drive, Bethesda, Maryland 20892, United States.
authors.forename: Sudhanshu
authors.initials: S
authors.lastname: Shukla
authors.affiliation: Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institute of Health , 10 Center Drive, Bethesda, Maryland 20892, United States.
authors.forename: Uma T
authors.initials: UT
authors.lastname: Shankavaram
authors.affiliation: Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institute of Health , 10 Center Drive, Bethesda, Maryland 20892, United States.
authors.forename: Phuongmai
authors.initials: P
authors.lastname: Nguyen
authors.affiliation: Proteomics and Mass Spectrometry Core Facility, Penn State College of Medicine , 500 University Drive, MC: H093, Hershey, Pennsylvania 17033, United States.
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Stanley
authors.affiliation: Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institute of Health , 10 Center Drive, Bethesda, Maryland 20892, United States.
authors.forename: DeeDee K
authors.initials: DK
authors.lastname: Smart
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000528:radiation effects*; D001923:Brain Chemistry; D004195:Disease Models, Animal; D034284:Dynamin I / Q000235:genetics / Q000378:metabolism; D005720:Gamma Rays; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D053858:Metabolic Networks and Pathways / Q000528:radiation effects*; D051379:Mice; D018345:Mice, Knockout; D058977:Molecular Sequence Annotation; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000235:genetics / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020543:Proteome / Q000235:genetics* / Q000378:metabolism; D056565:Sirtuin 2 / Q000172:deficiency / Q000235:genetics*; D050825:Synaptosomal-Associated Protein 25 / Q000235:genetics / Q000378:metabolism; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C558298:Mapt protein, mouse; C571327:Mog protein, mouse; D063308:Myelin-Oligodendrocyte Glycoprotein; D020543:Proteome; C494209:Snap25 protein, mouse; D050825:Synaptosomal-Associated Protein 25; D016875:tau Proteins; C418743:Sirt2 protein, mouse; D056565:Sirtuin 2; D034284:Dynamin I
keywords: SIRT2; brain; iTRAQ; neurodegeneration; neurotoxicity; radiation