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Reduced proteasomal activity contributes to the accumulation of carbonylated proteins in chronic experimental autoimmune encephalomyelitis
Author(s) -
Zheng Jianzheng,
Bizzozero Oscar A.
Publication year - 2010
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2010.07062.x
Subject(s) - proteasome , experimental autoimmune encephalomyelitis , myelin oligodendrocyte glycoprotein , proteolysis , glial fibrillary acidic protein , ubiquitin , chemistry , protein degradation , myelin basic protein , encephalomyelitis , immunology , microbiology and biotechnology , biology , biochemistry , myelin , inflammation , multiple sclerosis , endocrinology , central nervous system , enzyme , immunohistochemistry , gene
J. Neurochem. (2010) 115, 1556–1567. Abstract We have recently shown that several carbonylated proteins, including glial fibrillary acidic protein, β‐actin and β‐tubulin, accumulate within cerebellar astrocytes during the chronic phase of myelin‐oligodendrocyte glycoprotein (MOG) 35‐55 peptide‐induced experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice. As protein carbonyls cannot be repaired and there is less oxidative stress in chronic than in acute EAE, we hypothesized that the accumulation of carbonylated proteins in these animals may be due to a defect in the degradation of the modified proteins. Alternatively, oxidized proteins in chronic EAE mice may be more resistant to proteolysis. Using lipopolysaccharide‐stimulated astrocytes and several protease inhibitors we identified the 20S proteasome as the proteolytic system responsible for the elimination of most oxidized proteins. We also discovered that the chymotrysin‐like and caspase‐like activities of the 20S proteasome are impaired in chronic EAE, while the amount of proteasome was unchanged. Proteasome failure in these animals was confirmed by the build‐up of ubiquitinated proteins, mostly within astrocytes. In a cell‐free system, carbonylated proteins from EAE mice with acute and chronic disease seem to be equally sensitive to proteasomal degradation. Altogether, the results support the notion that diminished activity of the 20S proteasome is a major contributor to the accumulation of carbonylated proteins in astrocytes of chronic EAE mice.