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

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• 作者：Sudhanshu Shukla ; Uma T. Shankavaram ; Phuongmai Nguyen ; Bruce A. Stanley ; DeeDee K. Smart
• 刊名：Journal of Proteome Research
• 出版年：2015
• 出版时间：October 2, 2015
• 年：2015
• 卷：14
• 期：10
• 页码：4104-4117
• 全文大小：815K
• ISSN：1535-3907

文摘

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鈥檚, Parkinson鈥檚, and Alzheimer鈥檚 were acutely affected by radiation within 72 h of treatment. Although loss of Sirt2 preferentially affected both Huntington鈥檚 and Parkinson鈥檚 pathways, WBRT most significantly affected Huntington鈥檚-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.