Radiation-Induced Alteration of the Brain Proteome: Understanding the Role of the Sirtuin 2 Deacetylase in a Murine Model

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 <i>Sirt2</i> 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 <i>Sirt2</i> 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 <i>Sirt2</i> preferentially affected both Huntington’s and Parkinson’s pathways, WBRT most significantly affected Huntington’s-related proteins in the absence of <i>Sirt2</i>. Identical protein expression patterns were identified in Mog following WBRT in both <i>Sirt2</i> 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 <i>Sirt2</i> can have significant effects on the brain proteome and its response to ionizing radiation

Radiation-Induced Alteration of the Brain Proteome: Understanding the Role of the Sirtuin 2 Deacetylase in a Murine Model

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 <i>Sirt2</i> 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 <i>Sirt2</i> 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 <i>Sirt2</i> preferentially affected both Huntington’s and Parkinson’s pathways, WBRT most significantly affected Huntington’s-related proteins in the absence of <i>Sirt2</i>. Identical protein expression patterns were identified in Mog following WBRT in both <i>Sirt2</i> 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 <i>Sirt2</i> can have significant effects on the brain proteome and its response to ionizing radiation