Restructuring the neuronal stress response with anti-glucocorticoid gene delivery.
Glucocorticoids, the adrenal steroids released during stress, compromise the ability of neurons to survive neurological injury. In contrast, estrogen protects neurons against such injuries. We designed three genetic interventions to manipulate the actions of glucocorticoids, which reduced their deleterious effects in both in vitro and in vivo rat models. The most effective of these interventions created a chimeric receptor combining the ligand-binding domain of the glucocorticoid receptor and the DNA-binding domain of the estrogen receptor. Expression of this chimeric receptor reduced hippocampal lesion size after neurological damage by 63% and reversed the outcome of the stress response by rendering glucocorticoids protective rather than destructive. Our findings elucidate three principal steps in the neuronal stress-response pathway, all of which are amenable to therapeutic intervention.
Kaufer
D
D
Department of Biological Sciences, Stanford University, Stanford, California, USA. danielak@stanford.edu
Ogle
W O
WO
Pincus
Z S
ZS
Clark
K L
KL
Nicholas
A C
AC
Dinkel
K M
KM
Dumas
T C
TC
Ferguson
D
D
Lee
A L
AL
Winters
M A
MA
Sapolsky
R M
RM
D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western / Q000379:methods; D002452:Cell Count / Q000379:methods; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D046508:Culture Techniques; D047628:Estrogen Receptor alpha; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D005938:Glucocorticoids / Q000037:antagonists & inhibitors*; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D006801:Humans; D017874:Immediate-Early Proteins; D007150:Immunohistochemistry / Q000379:methods; D007211:Indoles; D007608:Kainic Acid / Q000633:toxicity; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008958:Models, Molecular; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013312:Stress, Physiological / Q000235:genetics / Q000378:metabolism*; D019076:Transgenes; D014178:Translocation, Genetic / Q000502:physiology; D000099184:Serum-Glucocorticoid Regulated Kinases
D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; D047628:Estrogen Receptor alpha; D005346:Fibroblast Growth Factors; D005938:Glucocorticoids; D017874:Immediate-Early Proteins; D007211:Indoles; D007608:Kainic Acid; D008869:Microtubule-Associated Proteins; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D011965:Receptors, Glucocorticoid; D016194:Receptors, N-Methyl-D-Aspartate; D011993:Recombinant Fusion Proteins; D000099184:Serum-Glucocorticoid Regulated Kinases; C506487:ESR1 protein, human; C464436:NR2D NMDA receptor; C007293:DAPI