BAG1 over-expression in brain protects against stroke.
The co-chaperone BAG1 binds and regulates 70 kDa heat shock proteins (Hsp70/Hsc70) and exhibits cytoprotective activity in cell culture models. Recently, we observed that BAG1 expression is induced during neuronal differentiation in the developing brain. However, the in vivo effects of BAG1 during development and after maturation of the central nervous system have never been examined. We generated transgenic mice over-expressing BAG1 in neurons. While brain development was essentially normal, cultured cortical neurons from transgenic animals exhibited resistance to glutamate-induced, apoptotic neuronal death. Moreover, in an in vivo stroke model involving transient middle cerebral artery occlusion, BAG1 transgenic mice demonstrated decreased mortality and substantially reduced infarct volumes compared to wild-type littermates. Interestingly, brain tissue from BAG1 transgenic mice contained higher levels of neuroprotective Hsp70/Hsc70 protein but not mRNA, suggesting a potential mechanism whereby BAG1 exerts its anti-apoptotic effects. In summary, BAG1 displays potent neuroprotective activity in vivo against stroke, and therefore represents an interesting target for developing new therapeutic strategies including gene therapy and small-molecule drugs for reducing brain injury during cerebral ischemia and neurodegenerative diseases.
Kermer
Pawel
P
Department of Neurology, University of Goettingen, Germany.
Digicaylioglu
Murat H
MH
Kaul
Marcus
M
Zapata
Juan M
JM
Krajewska
Maryla
M
Stenner-Liewen
Frank
F
Takayama
Shinichi
S
Krajewski
Stan
S
Lipton
Stuart A
SA
Reed
John C
JC
D000818:Animals; D000831:Animals, Newborn; D015152:Blotting, Northern; D015153:Blotting, Western; D001921:Brain / Q000033:anatomy & histology / Q000378:metabolism* / Q000473:pathology; D001923:Brain Chemistry; D016923:Cell Death; D002478:Cells, Cultured; D004268:DNA-Binding Proteins; D004195:Disease Models, Animal; D006360:Heat-Shock Proteins / Q000378:metabolism; D007150:Immunohistochemistry; D020244:Infarction, Middle Cerebral Artery / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D016133:Polymerase Chain Reaction / Q000379:methods; D011506:Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D012039:Regional Blood Flow; D013194:Staining and Labeling; D020521:Stroke / Q000378:metabolism* / Q000473:pathology; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
C091732:BCL2-associated athanogene 1 protein; D004268:DNA-Binding Proteins; D006360:Heat-Shock Proteins; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D011506:Proteins; D012333:RNA, Messenger; D014157:Transcription Factors