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 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.