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

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Title: Role of BCL-XL in cell death after spinal cord injury
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
URI: http : / /hdl .handle .net /2152 .3 /293
Date: 2006-12-11


Role of BCL-XL in cell death after spinal cord injury. Doctoral dissertation, The University of Texas Medical Branch. Available electronically from http : / /hdl .handle .net /2152 .3 /293 .

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