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      Increased carbonylation, protein aggregation and apoptosis in the spinal cord of mice with experimental autoimmune encephalomyelitis

      research-article
      * , * , , * , 1
      ASN NEURO
      American Society for Neurochemistry
      apoptosis, autophagy, experimental autoimmune encephalomyelitis, oxidative stress, protein aggregation, protein carbonylation, proteostasis, AMC, 7-aminomethyl-4-coumarin, APC, adenomatous polyposis coli protein C-terminus, CFA, complete Freund’s adjuvant, CNS, cenral nervous system, DAPI, 4′,6-diamidino-2-phenylindole, DNP, 2,4-dinitrophenyl, DNPH, 2,4-dinitrophenylhydrazine, DPI, days post-immunization, EAE, experimental autoimmune encephalomyelitis, ECL, enhanced chemiluminescence, GFAP, glial fibrillary-associated protein, HRP, horseradish peroxidase, LC3, microtubule-associated protein light chain 3, MOG, myelin-oligodendrocyte glycoprotein, MS, multiple sclerosis, TBARS, thiobarbituric acid-reacting substances, TUNEL, terminal deoxynucleotidyltransferase-mediated dUTP nick-end labelling

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          Abstract

          Previous work from our laboratory implicated protein carbonylation in the pathophysiology of both MS (multiple sclerosis) and its animal model EAE (experimental autoimmune encephalomyelitis). Subsequent in vitro studies revealed that the accumulation of protein carbonyls, triggered by glutathione deficiency or proteasome inhibition, leads to protein aggregation and neuronal cell death. These findings prompted us to investigate whether their association can be also established in vivo. In the present study, we characterized protein carbonylation, protein aggregation and apoptosis along the spinal cord during the course of MOG (myelin-oligodendrocyte glycoprotein) 35–55 peptide-induced EAE in C57BL/6 mice. The results show that protein carbonyls accumulate throughout the course of the disease, albeit by different mechanisms: increased oxidative stress in acute EAE and decreased proteasomal activity in chronic EAE. We also show a temporal correlation between protein carbonylation (but not oxidative stress) and apoptosis. Furthermore, carbonyl levels are significantly higher in apoptotic cells than in live cells. A high number of juxta-nuclear and cytoplasmic protein aggregates containing the majority of the oxidized proteins are present during the course of EAE. The LC3 (microtubule-associated protein light chain 3)-II/LC3-I ratio is significantly reduced in both acute and chronic EAE indicating reduced autophagy and explaining why aggresomes accumulate in this disorder. Taken together, the results of the present study suggest a link between protein oxidation and neuronal/glial cell death in vivo, and also demonstrate impaired proteostasis in this widely used murine model of MS.

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          Most cited references55

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          Cellular strategies for controlling protein aggregation.

          The aggregation of misfolded proteins is associated with the perturbation of cellular function, ageing and various human disorders. Mounting evidence suggests that protein aggregation is often part of the cellular response to an imbalanced protein homeostasis rather than an unspecific and uncontrolled dead-end pathway. It is a regulated process in cells from bacteria to humans, leading to the deposition of aggregates at specific sites. The sequestration of misfolded proteins in such a way is protective for cell function as it allows for their efficient solubilization and refolding or degradation by components of the protein quality-control network. The organized aggregation of misfolded proteins might also allow their asymmetric distribution to daughter cells during cell division.
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            Oxidative damage in multiple sclerosis lesions

            Multiple sclerosis is a chronic inflammatory disease of the central nervous system, associated with demyelination and neurodegeneration. The mechanisms of tissue injury are currently poorly understood, but recent data suggest that mitochondrial injury may play an important role in this process. Since mitochondrial injury can be triggered by reactive oxygen and nitric oxide species, we analysed by immunocytochemistry the presence and cellular location of oxidized lipids and oxidized DNA in lesions and in normal-appearing white matter of 30 patients with multiple sclerosis and 24 control patients without neurological disease or brain lesions. As reported before in biochemical studies, oxidized lipids and DNA were highly enriched in active multiple sclerosis plaques, predominantly in areas that are defined as initial or ‘prephagocytic’ lesions. Oxidized DNA was mainly seen in oligodendrocyte nuclei, which in part showed signs of apoptosis. In addition, a small number of reactive astrocytes revealed nuclear expression of 8-hydroxy-d-guanosine. Similarly, lipid peroxidation-derived structures (malondialdehyde and oxidized phospholipid epitopes) were seen in the cytoplasm of oligodendrocytes and some astrocytes. In addition, oxidized phospholipids were massively accumulated in a fraction of axonal spheroids with disturbed fast axonal transport as well as in neurons within grey matter lesions. Neurons stained for oxidized phospholipids frequently revealed signs of degeneration with fragmentation of their dendritic processes. The extent of lipid and DNA oxidation correlated significantly with inflammation, determined by the number of CD3 positive T cells and human leucocyte antigen-D expressing macrophages and microglia in the lesions. Our data suggest profound oxidative injury of oligodendrocytes and neurons to be associated with active demyelination and axonal or neuronal injury in multiple sclerosis.
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              Role of oxidative carbonylation in protein quality control and senescence.

              Proteins can become modified by a large number of reactions involving reactive oxygen species. Among these reactions, carbonylation has attracted a great deal of attention due to its irreversible and unrepairable nature. Carbonylated proteins are marked for proteolysis by the proteasome and the Lon protease but can escape degradation and form high-molecular-weight aggregates that accumulate with age. Such carbonylated aggregates can become cytotoxic and have been associated with a large number of age-related disorders, including Parkinson's disease, Alzheimer's disease, and cancer. This review focuses on the generation of and defence against protein carbonyls and speculates on the potential role of carbonylation in protein quality control, cellular deterioration, and senescence.
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                Author and article information

                Journal
                ASN Neuro
                ASN Neuro
                ASN
                ASN NEURO
                American Society for Neurochemistry (9037 Ron Den Lane, Windermere, FL 34786, U.S.A. )
                1759-0914
                14 March 2013
                8 April 2013
                2013
                : 5
                : 2
                : e00111
                Affiliations
                *Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, NM, U.S.A.
                †Department of Neurosciences, University of New Mexico Health Sciences Center, Albuquerque, NM, U.S.A.
                Author notes
                1To whom correspondence should be addressed (email obizzozero@ 123456salud.unm.edu ).
                Article
                AN20120088
                10.1042/AN20120088
                3620690
                23489322
                18cdbcea-3432-4969-9897-de8705ae40e4
                © 2013 The Author(s)

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial Licence (NC-BY) ( http://creativecommons.org/licenses/by-nc/2.5/) which permits unrestricted non-commercial use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 12 December 2012
                : 4 March 2013
                : 14 March 2013
                Page count
                Figures: 10, References: 67, Pages: 13
                Categories
                Research Article
                S3

                Neurosciences
                amc, 7-aminomethyl-4-coumarin,apc, adenomatous polyposis coli protein c-terminus,apoptosis,autophagy,cfa, complete freund’s adjuvant,cns, cenral nervous system,dapi, 4′,6-diamidino-2-phenylindole,dnp, 2,4-dinitrophenyl,dnph, 2,4-dinitrophenylhydrazine,dpi, days post-immunization,eae, experimental autoimmune encephalomyelitis,ecl, enhanced chemiluminescence,experimental autoimmune encephalomyelitis,gfap, glial fibrillary-associated protein,hrp, horseradish peroxidase,lc3, microtubule-associated protein light chain 3,mog, myelin-oligodendrocyte glycoprotein,ms, multiple sclerosis,oxidative stress,protein aggregation,protein carbonylation,proteostasis,tbars, thiobarbituric acid-reacting substances,tunel, terminal deoxynucleotidyltransferase-mediated dutp nick-end labelling

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