p53-Mediated oligodendrocyte apoptosis initiates demyelination after compressed spinal cord injury by enhancing ER-mitochondria interaction and E2F1 expression

• Published in: Neuroscience letters Vol. 644; pp. 55 - 61
• Main Authors: Ma, Lan, Yu, Hai-jun, Gan, Sheng-wei, Gong, Rui, Mou, Ke-jie, Xue, Jun, Sun, Shan-quan
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 22.03.2017
• Subjects: Animals; Apoptosis - physiology; Compressed spinal cord injury; Demyelinating Diseases - metabolism; Demyelinating Diseases - pathology; Demyelination; E2F1; E2F1 Transcription Factor - biosynthesis; Endoplasmic Reticulum - metabolism; Female; Mitochondria - metabolism; Myelin basic protein; Oligodendrocyte; Oligodendroglia - metabolism; Oligodendroglia - pathology; p53; Rats; Rats, Sprague-Dawley; Spinal Cord Compression - pathology; Tumor Suppressor Protein p53 - metabolism; Compressed spinal cord injury; Oligodendrocyte; PFT-μ; L1; Demyelination; SCI; E2F1; CSCI; MBP; ER; Myelin basic protein; p53
• ISSN: 0304-3940; 1872-7972
• DOI: 10.1016/j.neulet.2017.02.038

•Demyelination occurs in part due to oligodendrocytes apoptosis.•p53 activates E2F1, which then causes demyelination.•ER–mitochondria interaction is involved in demyelination.•PFT-μ can reduce apoptosis by inhibiting the ER–mitochondrial pathway and E2F1 expression. 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.