Astrocyte-specific overexpression of Nrf2 protects striatal neurons from mitochondrial complex II inhibition.
Nuclear factor E2-related factor 2 (Nrf2) is a transcription factor that is known to regulate a variety of cytoprotective genes through the antioxidant response element (ARE). This endogenous response is one of the major pathways by which cells are protected from xenobiotic or innate oxidative insults. Furthermore, in neural systems, astrocyte-specific activation of Nrf2 is known to protect neurons. In previous work, our laboratory found that Nrf2 protects from intrastriatal injections of the mitochondrial complex II inhibitor malonate. Here, we extend these results to show that multiple methods of astrocyte-specific Nrf2 overexpression provide protection from neurotoxicity in vivo. GFAP-Nrf2 transgenic mice are significantly more resistant to malonate lesioning. This outcome is associated with an increased basal resistance, but more so, an enhanced Nrf2 response to lesioning that attenuated the ensuing neurotoxicity. Furthermore, striatal transplantation of neuroprogenitor cells overexpressing Nrf2 that differentiate into astrocytes after grafting also significantly reduced malonate toxicity. Overall, these data establish that enhanced astrocytic Nrf2 response and Nrf2 preconditioning are both sufficient to protect from acute lesions from mitochondrial complex II inhibition.
Calkins
Marcus J
MJ
Molecular and Environmental Toxicology Center, University of Wisconsin, Madison, Wisconsin 53705, USA.
Vargas
Marcelo R
MR
Johnson
Delinda A
DA
Johnson
Jeffrey A
JA
D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism* / Q000637:transplantation; D002454:Cell Differentiation; D017690:Cell Transplantation; D003342:Corpus Striatum / Q000187:drug effects / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000633:toxicity; D015870:Gene Expression / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D008314:Malonates / Q000633:toxicity; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism; D013385:Succinate Dehydrogenase / Q000037:antagonists & inhibitors* / Q000378:metabolism
D004791:Enzyme Inhibitors; D008314:Malonates; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D012333:RNA, Messenger; C030290:malonic acid; D013385:Succinate Dehydrogenase; D005978:Glutathione