title: The hGFAP-driven conditional TSPO knockout is protective in a mouse model of multiple sclerosis.
abstract: The mitochondrial translocator protein (TSPO) has been implicated in CNS diseases. Here, we sought to determine the specific role of TSPO in experimental autoimmune encephalomyelitis (EAE), the most studied animal model of multiple sclerosis (MS). To fundamentally elucidate the functions of TSPO, we first developed a viable TSPO knockout mouse. A conditional TSPO knockout mouse was generated by utilizing the Cre-Lox system. We generated a TSPO floxed mouse, and then crossed this mouse with a Cre recombinase expressing mouse driven by the human glial fibrillary acidic protein (hGFAP) promoter. The resultant mouse was a neural linage line specific TSPO knockout. The loss of TSPO in the CNS did not result in overt developmental defects or phenotypes. The TSPO-/- mouse showed a decrease in GFAP expression, correlating with a decrease in astrogliosis in response to neural injury during EAE. This decrease in astrogliosis was also witnessed in the lessening of severity of EAE clinical scoring, indicating an in vivo functional role for TSPO in suppressing EAE. The TSPO-/- mouse could be a useful tool in better understanding the role of TSPO in CNS disease, and our results implicate TSPO as a potential therapeutic target in MS.
authors.affiliation: Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, CA, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Daugherty
authors.affiliation: Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, CA, USA.
authors.forename: Olga
authors.initials: O
authors.lastname: Chechneva
authors.affiliation: Shriners Institute for Pediatric Regenerative Medicine, Sacramento, CA, USA.
authors.forename: Florian
authors.initials: F
authors.lastname: Mayrhofer
authors.affiliation: Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, CA, USA.|Shriners Institute for Pediatric Regenerative Medicine, Sacramento, CA, USA.|Medical College, Hubei University of Arts and Science, Xiangyang, Hubei, China.
authors.forename: Wenbin
authors.initials: W
authors.lastname: Deng
mesh_terms: D000818:Animals; D002490:Central Nervous System / Q000473:pathology; D054357:Chemokine CXCL10 / Q000235:genetics; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics* / Q000473:pathology*; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics*; D007249:Inflammation / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009103:Multiple Sclerosis / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D018079:Receptors, GABA / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
chemical_list: C463819:Bzrp protein, mouse; D054357:Chemokine CXCL10; C485433:Cxcl10 protein, mouse; D005904:Glial Fibrillary Acidic Protein; D012333:RNA, Messenger; D018079:Receptors, GABA; D014409:Tumor Necrosis Factor-alpha; C528900:glial fibrillary astrocytic protein, mouse