title: Mitochondrial-targeted human catalase affords neuroprotection from proton irradiation.
abstract: Significant past work has linked radiation exposure of the CNS to elevated levels of oxidative stress and inflammation. These secondary reactive processes are both dynamic and persistent and are believed to compromise the functionality of the CNS, in part, by disrupting endogenous neurogenesis in the hippocampus. While evidence has shown neurogenesis to be sensitive to irradiation and redox state, the mechanistic basis underlying these effects is incompletely understood. To clarify the role of reactive oxygen species (ROS) in mediating radiation-induced changes in neurogenesis we have analyzed transgenic mice that overexpress human catalase localized to the mitochondria. With this model, we investigated the consequences of low dose and clinically relevant proton irradiation on neurogenesis, and how that process is modified in response to genetic disruption of mitochondrial ROS levels. In unirradiated animals, basal neurogenesis was improved significantly by reductions in mitochondrial ROS. In animals subjected to proton exposure, hippocampal progenitor cell proliferation was attenuated significantly by overexpression of human catalase in the mitochondria. Furthermore, expression of the MCAT transgene significantly improved neurogenesis in WT animals after low-dose proton exposure (0.5 Gy), with similar trends observed at higher dose (2 Gy). Our report documents for the first time the impact of proton irradiation on hippocampal neurogenesis, and the neuroprotective properties of reducing mitochondrial ROS through the targeted overexpression of catalase.
authors.affiliation: Department of Radiation Oncology, University of California, Irvine, California, USA.
authors.forename: Alicia C
authors.initials: AC
authors.lastname: Liao
authors.forename: Brianna M
authors.initials: BM
authors.lastname: Craver
authors.forename: Bertrand P
authors.initials: BP
authors.lastname: Tseng
authors.forename: Katherine K
authors.initials: KK
authors.lastname: Tran
authors.forename: Vipan K
authors.initials: VK
authors.lastname: Parihar
authors.forename: Munjal M
authors.initials: MM
authors.lastname: Acharya
authors.forename: Charles L
authors.initials: CL
authors.lastname: Limoli
mesh_terms: D000818:Animals; D002374:Catalase / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation / Q000528:radiation effects; D002490:Central Nervous System / Q000254:growth & development / Q000528:radiation effects*; D015870:Gene Expression / Q000235:genetics; D006624:Hippocampus / Q000254:growth & development / Q000528:radiation effects*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism / Q000528:radiation effects; D055495:Neurogenesis / Q000528:radiation effects*; D018696:Neuroprotective Agents / Q000378:metabolism; D018384:Oxidative Stress; D011522:Protons; D017382:Reactive Oxygen Species / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism / Q000528:radiation effects
chemical_list: D018696:Neuroprotective Agents; D011522:Protons; D017382:Reactive Oxygen Species; D002374:Catalase