Role of BCL-XL in cell death after spinal cord injury

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Role of BCL-XL in cell death after spinal cord injury

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dc.contributor.advisor J.Regino Perez-Polo en_US
dc.creator DIANA M. CITTELLY en_US
dc.date.accessioned 2011-12-20T16:05:44Z
dc.date.available 2009-06-09 en_US
dc.date.available 2011-12-20T16:05:44Z
dc.date.created 2006-12-14 en_US
dc.date.issued 2006-12-11 en_US
dc.identifier.other etd-12142006-152807 en_US
dc.identifier.uri http://hdl.handle.net/2152.3/293
dc.description.abstract Long term functional impairment after rat spinal cord injury (SCI) results from secondary apoptosis regulated in part, by SCI-induced decreases in protein levels of the anti-apoptotic protein Bcl-xL. In this dissertation, I assessed the role that Bcl-xL subcellular re-routing and post-translational phosphorylation play in SCI-induced Bcl-xL decreases, and evaluated the therapeutic potential of Bcl-xL-administration after SCI. Immunohistochemical analysis showed non-phosphorylated Bcl-xL in neurons and oligodendrocytes, but not in astrocytes and microglia. Bcl-xL levels decreased in mitochondria, endoplasmic reticulum, nuclei and cytosolic extracts during the first 24h after SCI, but with a different time course for each organelle; suggesting an independent regulation of Bcl-xL shuttling from the cytosol to each compartment in the injured spinal cords. A membrane-bound phosphorylated form of Bcl-xL (P-ser62-Bcl-xL) was found in neurons in the uninjured SC. SCI did not affect P-ser62-Bcl-xL levels in organelles; however, P-ser62-Bcl-xL appeared in the cytosol early after SCI, suggesting a role for phosphorylation in SCI-induced decreases of Bcl-xL levels. Vinblastine-induced apoptosis of neuronal PC12 cells, showed that cytosolic phosphorylated Bcl-xL correlated with apoptotic cell death of neurons, suggestive of Bcl-xL-phosphorylation as a pro-apoptotic event. I found that activated microglia/macrophages robustly expressed Bcl-xL, 7 days after SCI, and a fraction of this population undergoing apoptosis, expressed P-ser62-Bcl-xL. Therefore, phosphorylation of Bcl-xL may have two opposite effects in injured spinal cords: (a) it may decrease levels of the anti-apoptotic Bcl-xL in neurons and therefore contribute to their death and, (b) it may regulate apoptosis in activated microglia/macrophages, thus curtailing the inflammatory cascades associated with SCI.\r\nTo counteract SCI-induced decreases in Bcl-xL and resulting apoptosis, I used a fusion protein made up of the TAT protein transduction domain and the Bcl-xL protein (Tat-Bcl-xL), or to its anti-apoptotic domain BH4 (Tat-BH4). Intrathecal delivery of Tat-Bcl-xL, or Tat-BH4 for 24h or 7 days after SCI, resulted in a significant decrease in apoptosis at the site of injury. However, the 7 day delivery of Tat-Bcl-xL or Tat-BH4 impaired locomotor recovery beyond the drug delivery time. Here I show that the 7 day application of Tat-Bcl-xL or Tat-BH4 increased microglia/macrophage activation and/or survival associated with an increase in neuronal losses. These results suggest that the anti-apoptotic treatment may shift neuronal apoptosis to necrosis, and initiate an inflammatory response (microglial activation) in SCI rats. As a result, Tat-Bcl-xL/Tat-BH4-induced increases in proinflammatory reactions may amplify SCI-induced neuronal cell death and additionally impair functional recovery. Given that microglial activation and inflammation are main players in shaping pathological outcomes after SCI, these results suggest that the therapeutic potential of Tat-Bcl-xL or Tat-BH4 in injured spinal cords may be limited. Moreover, chronic treatment of SCI with Tat-Bcl-xL or other anti-apoptotic treatments targeting Bcl-xL could be detrimental.\r\n en_US
dc.format.medium electronic en_US
dc.language.iso eng en_US
dc.rights Copyright © is held by the author. Presentation of this material on the TDL web site by The University of Texas Medical Branch at Galveston was made possible under a limited license grant from the author who has retained all copyrights in the works. en_US
dc.subject Tat-BH4 en_US
dc.subject Tat-Bcl-xL en_US
dc.subject subcellular localization en_US
dc.subject spinal cord trauma en_US
dc.subject phosphorylation en_US
dc.subject neuronal death en_US
dc.subject microglial activation en_US
dc.subject Apoptosis en_US
dc.subject anti-apoptotic therapy en_US
dc.title Role of BCL-XL in cell death after spinal cord injury en_US
dc.type.material text en_US
dc.type.genre dissertation en_US
thesis.degree.name PhD en_US
thesis.degree.level Doctoral en_US
thesis.degree.grantor The University of Texas Medical Branch en_US
thesis.degree.department Cell Biology en_US
dc.contributor.committeeMember Olivera Nesic-Taylor en_US
dc.contributor.committeeMember Jacqueline Bresnahan en_US
dc.contributor.committeeMember Golda Leonard en_US
dc.contributor.committeeMember Giulio Taglialatela en_US

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