title: p53-Mediated oligodendrocyte apoptosis initiates demyelination after compressed spinal cord injury by enhancing ER-mitochondria interaction and E2F1 expression.
abstract: Oligodendrocyte apoptosis mediated demyelination is a pathological change characteristic of compressed spinal cord injury (CSCI). However, the mechanism of demyelination due to oligodendrocyte apoptosis is not known. In this study, after successfully establishing a rat CSCI model using a custom-made compressor, we investigated the pathological changes, MBP expression, as well as apoptosis-related protein (p53, active caspase-3) expression to determine whether or not apoptosis and demyelination occurred after injury. To understand the possible mechanism of oligodendrocyte apoptosis, caspase-12 and cytochrome C were analyzed to explore the relationship between oligodendrocyte apoptosis and endoplasmic reticulum(ER)-mitochondria interaction. The transcription factor, E2F1, was also detected by immunofluorescence and Western blot assays. The results showed that CSCI increased the expression levels of p53, E2F1 and active caspase-3 followed by the swelling and breakdown of myelin sheaths. The number of myelinated nerve fibers also decreased with down-regulated expression of MBP. Expression levels of caspase-12 and cytochrome C were enhanced along with a reduction in the number of oligodendrocytes. After treatment of CSCI in rats with Pifithrin-μ(PFT-μ), a specific inhibitor of p53, pathomorphological changes of myelin sheath improved significantly. Expression levels of E2F1, active caspase-3, caspase-12 and cytochrome C were down-regulated, consistent with reduced the number of apoptotic oligodendrocytes. These results demonstrated that over-expression of p53 could mediate oligodendrocyte apoptosis thus resulting in demyelination in two ways; by enhancing ER-mitochondria interaction and by triggering the E2F1 mediated apoptosis pathway.
authors.affiliation: Institute of Neuroscience, Chongqing Medical University, Chongqing, China.
authors.forename: Lan
authors.initials: L
authors.lastname: Ma
authors.affiliation: Institute of Neuroscience, Chongqing Medical University, Chongqing, China.
authors.forename: Hai-Jun
authors.initials: HJ
authors.lastname: Yu
authors.affiliation: Institute of Neuroscience, Chongqing Medical University, Chongqing, China.
authors.forename: Sheng-Wei
authors.initials: SW
authors.lastname: Gan
authors.affiliation: Institute of Neuroscience, Chongqing Medical University, Chongqing, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Gong
authors.affiliation: Bishan Hospital of the First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: Ke-Jie
authors.initials: KJ
authors.lastname: Mou
authors.affiliation: Bishan Hospital of the First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Xue
authors.affiliation: Institute of Neuroscience, Chongqing Medical University, Chongqing, China. Electronic address: sunsq2151@163.com.
authors.forename: Shan-Quan
authors.initials: SQ
authors.lastname: Sun
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D003711:Demyelinating Diseases / Q000378:metabolism* / Q000473:pathology; D050687:E2F1 Transcription Factor / Q000096:biosynthesis; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005260:Female; D008928:Mitochondria / Q000378:metabolism; D009836:Oligodendroglia / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013117:Spinal Cord Compression / Q000473:pathology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D050687:E2F1 Transcription Factor; C493755:E2f1 protein, rat; D016159:Tumor Suppressor Protein p53
keywords: Compressed spinal cord injury; Demyelination; E2F1; Myelin basic protein; Oligodendrocyte; p53