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Necrosis triggers multiple sclerosis

Posted on 26th Mar 2015 @ 8:27 AM

    Multiple sclerosis is a common central nervous system degenerative disease, primarily accompanied with reduced oligodendrocytes as well as demyelination . Although there are many research regarding multiple sclerosis, however the reduction mechanism of oligodendrocytes remains unclear currently . Due to the death of oligodendrocytes could cause the reduction of myelin and the degeneration in axons, resulting in the inevitable neurodegeneration, and exploration of oligodendrocyte cell death mechanism would contribute to providing clinical treatments for multiple sclerosis patients . Recently, Harvard Medical School Junying Yuan Research Group published their latest research regarding oligodendrocytes cell death mechanism in the journal of "cell report" . Firstly, in order to study the reason for oligodendrocytes glial cell death in patients lesions tissues , the researchers analyzed the activation situation of caspase 8 in patients samples . Surprisingly, compared to age-matched control group of samples, caspase P18 subunit levels in patients with multiple sclerosis significantly decreased , while the content of corresponding immature pro-caspase 8 increased significantly.This showed that the activity of caspase 8 in patients’ cortical tissue .

   Due to caspase 8 activity in cortical tissue mainly focused on microglial cells, whereas activation of caspase 8 was likely to trigger inflammation and cell death signals. Thus, the researcher suspected that microglia in patients may start necrosis program.   And then , researchers analyzed the gene expression in the patient and control samples by microarray. It was shown that most of the up-regulated genes involved in cell death signal transduction . By WB method , the researchers detected the phosphorylation of crucial protein RIPK1 involving in cell death regulation as well as the RIPK3 in patients samples and the control samples . It was shown that two types of proteins were significantly phosphorylated in patients samples , namely the activation of mark, while the control group didn’t show significant phosphorylation . In addition, the researchers also found that RIPK3 significantly interacted with RIPK1 in patients samples , which was the essential step for them to play their functions.In addition, investigator also found that RIPK3 interacted protein MLKL was also a crucial factor in the implementation of signal necrosis , it occurred significant diversity in patient sample. These results proved cell necrosis occurred in the lesion tissues of patients with multiple sclerosis.

   To demonstrate RIPK1&RIPK3 involved signal regulated the death of oligodendrocyte cell in vivo, the researchers utilized cuprizone established mouse oligodendrocytes demyelination model. After a period of administration , the researchers found that oligodendrocytes in mice appeared RIPK1 upregulation. And then independent caspase cell death phenomenon occurred. On this basis, if added RIPK1 inhibitor, it is possible to effectively inhibit oligodendrocyte death. Finally , the researchers compared the response of wild-type mice and RIPK3 mice under cuprizone stimulation, results showed that: mutant mice showed considerable resistance to cuprizone. The researchers also used mice meningitis viral model to perform in vivo experiment , it was found that RIPK1 inhibitor could effectively alleviate the necrosis of oligodendrocytes, and RIPK1 inhibitors could also inhibit the TNF-a-induced oligodendrocytes necrosis in vitro. In summary, the researchers demonstrated pligodendrocyte necrosis phenomenon and signal-regulated process in patients with multiple sclerosis through a series of experiments , which provides new clues for the development of clinical treatment , such as ACAT1 http://www.bioabb.com/products/ACAT1.html therapy .