Remarkable increases of α1-antichymotrypsin in brain tissues of rodents during prion infection

Chen, Cao; Xu, Xiao-Feng; Zhang, Ren-Qing; Ma, Yue; Lv, Yan; Li, Jian-Le; Shi, Qiang; Xiao, Kang; Sun, Jing; Yang, Xiaodong; Shi, Qi; Dong, Xiao‐Ping

doi:10.1080/19336896.2017.1349590

Cited by 9 publications

(10 citation statements)

References 40 publications

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“…Another possibility is related with the gradual appearances of neuropathological abnormalities, such as PrP Sc deposit, astrogliosis and activated microglia in the brain tissues. Our data here and in other previous studies [8,37,38] demonstrate that the amounts of PrP Sc in the samples of mid-early stage (80 dpi) are remarkably less than in that of mid-late (120 dpi) and end (180 dpi) stage of those two scrapie infected mouse models. Meanwhile, signi cant increases of GFAP-and Iba1-signals are also detected since mid-late stage.…”

Section: Discussionsupporting

confidence: 74%

Global profiles of a cetylated proteins in the brains of scrapie agents 139A- and ME7-infected mice collected at mid-early, mid-late and terminal stage

Shi¹,

Chen²,

Maimaitiming³

et al. 2020

Preprint

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BackgroundAcetylation is a reversible post-translational modification in eukaryotic and prokaryotic cells, actively participating in the regulation for biological functions and in the pathogenesis of diseases.MethodsThe acetylated proteins from the cortex regions of scrapie agents 139A- and ME7-infected mice collected at mid-early (80 days post-infection, dpi), mid-late (120 dpi) and terminal stage (180 dpi) were extracted. The global profiles of the brain acetylated proteins were assayed with proteomic mass spectrometry. The acetylated peptides whose levels were >1.5-fold higher or lower than that of age-matched normal controls were considered as differentially expressed acetylated peptides (DEAPs).ResultsA total of 1,485 acetylated peptides were identified. 118, 42 and 51 DEAPs were in the brains of 139A-80 dpi, 120 dpi and 180 dpi, while 390, 227 and 75 DEAPs were in those of ME7-80 dpi, 120 dpi and 180 dpi, respectively. Overwhelming majority of the DEAPs in mid-early stage was down-regulated, while more portions of DEAPs in mid-late and late stage were up-regulated. Approximately 22.1% (328/1485) acetylated peptides were mitochondrial associated, which were mapped to 74 different proteins. Among them, 44 (59.5%) proteins showed differentially expressed at least at one tested time-point. KEEG pathways analysis identified 39, 13, 10 and 55, 25, 18 pathways in the samples of 80, 120 and 180 dpi of 139A- and ME7-infected mice as significantly changed (P<0.05), respectively. Six pathways were commonly involved in all tested samples, including carbon metabolism, metabolic pathways, biosynthesis of amino acids, glycolysis/gluconeogenesis, pyruvate metabolism and citrate cycle (TCA cycle). Moreover, dozens of steps in TAC cycle were affected via down-regulated acetylation for the relevant enzymes in the mid-early stage, while many steps were affected in the mid-late stage via up-regulated acetylation. In the late stage, the affected steps focused on up-regulated acetylation for succinate dehydrogenase, fumarate hydratase and malate dehydrogenase.ConclusionCollectively, Our data here illustrated a picture of global acetylation for brain proteins during prion infection, showing remarkably inhibiting acetylation in the early stage and relatively enhanced acetylation in the late stage.

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Section: Discussionsupporting

confidence: 74%

Global profiles of a cetylated proteins in the brains of scrapie agents 139A- and ME7-infected mice collected at mid-early, mid-late and terminal stage

Shi¹,

Chen²,

Maimaitiming³

et al. 2020

Preprint

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“…Significant increases of brain AQP1 and AQP4 are also observed in BSE-infected bovine-PrP transgenic mice at the final stage of disease, but not in the early and middle stage [23]. Actually, numerous abnormally changed proteins, regardless of up-or down-regulated, show the similar time-dependent alternative trends, which become more significant at the middle-late stage of prion infection [33][34][35][36][37][38], reflecting a gradual but persistent progression of neuropathology in prion disease.…”

Section: Discussionmentioning

confidence: 93%

Significant enhanced expressions of aquaporin-1, -4 and -9 in the brains of various prion diseases

Shi

Yang

et al. 2019

Prion

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Aquaporins (AQPs) are widely expressed in various types of tissues, among them AQP1, AQP4 and AQP9 are expressed predominately with relatively special distributing features in various brain regions. The aberrant changes of AQP1 and AQP4 have been observed in the brains of Alzheimer disease (AD). To evaluate the underlying alteration of brain AQPs in prion diseases, scrapie strains of 139A, ME7 and S15 infected mice were tested in this study. Western blots revealed markedly increased levels of AQP1, AQP4 and AQP9 in the brain tissues of all tested scrapie-infected mice collected at terminal stage. Analyses of the AQPs levels in the brain tissues collected at different time-points during incubation period showed time-dependent increased in 139A and ME7-infected mice, especially at the middle-late stage. The AQP1 levels also increased in the cortex regions of some human prion diseases, including the patients with sporadic Creutzfeldt-Jakob disease (CJD), fatal familial insomnia (FFI) and G114V genetic CJD (gCJD). Immunohistochemistry (IHC) assays verified that the AQPs-positive cells were astrocyte-like morphologically; meanwhile, numerous various sizes of AQPs-positive particles and dots were also observable in the brain sections of scrapie-infected mice. Immunofluorescent assays (IFAs) illustrated that the signals of AQPs colocalized with those of the GFAP positive proliferative astrocytes, and more interestingly, appeared to overlap also with the signals of PrP in the brains of scrapie-infected mice. Moreover, IHC assays with a commercial doublestain system revealed that distributing areas of AQPs overlapped not only with that of the activated large astrocytes, but also with that of abundantly deposited PrPSc in the brain tissues of scrapie murine models. Our data here propose the solid evidences that the expressions of brain AQP1, AQP4 and AQP9 are all aberrantly enhanced in various murine models of scrapie infection. The closely anatomical association between the accumulated AQPs and deposited PrPSc in the brain tissues indicates that the abnormally increased water channel proteins participate in the pathogenesis of prion diseases.

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“…Moreover, increased level of SerpinA3n mRNA has been found in different mouse prion disease models [ 23 – 28 ], where its expression progressively increases during the course of the disease [ 22 , 29 , 30 ]…”

Section: Introductionmentioning

confidence: 99%

Serpin Signatures in Prion and Alzheimer’s Diseases

et al. 2022

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Serpins represent the most broadly distributed superfamily of proteases inhibitors. They contribute to a variety of physiological functions and any alteration of the serpin-protease equilibrium can lead to severe consequences. SERPINA3 dysregulation has been associated with Alzheimer’s disease (AD) and prion diseases. In this study, we investigated the differential expression of serpin superfamily members in neurodegenerative diseases. SERPIN expression was analyzed in human frontal cortex samples from cases of sporadic Creutzfeldt-Jakob disease (sCJD), patients at early stages of AD–related pathology, and age-matched controls not affected by neurodegenerative disorders. In addition, we studied whether Serpin expression was dysregulated in two animal models of prion disease and AD.Our analysis revealed that, besides the already observed upregulation of SERPINA3 in patients with prion disease and AD, SERPINB1, SERPINB6, SERPING1, SERPINH1, and SERPINI1 were dysregulated in sCJD individuals compared to controls, while only SERPINB1 was upregulated in AD patients. Furthermore, we analyzed whether other serpin members were differentially expressed in prion-infected mice compared to controls and, together with SerpinA3n, SerpinF2 increased levels were observed. Interestingly, SerpinA3n transcript and protein were upregulated in a mouse model of AD. The SERPINA3/SerpinA3nincreased anti-protease activity found in post-mortem brain tissue of AD and prion disease samples suggest its involvement in the neurodegenerative processes. A SERPINA3/SerpinA3n role in neurodegenerative disease-related protein aggregation was further corroborated by in vitro SerpinA3n-dependent prion accumulation changes. Our results indicate SERPINA3/SerpinA3n is a potential therapeutic target for the treatment of prion and prion-like neurodegenerative diseases.

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Remarkable increases of α1-antichymotrypsin in brain tissues of rodents during prion infection

Cited by 9 publications

References 40 publications

Global profiles of a cetylated proteins in the brains of scrapie agents 139A- and ME7-infected mice collected at mid-early, mid-late and terminal stage

Global profiles of a cetylated proteins in the brains of scrapie agents 139A- and ME7-infected mice collected at mid-early, mid-late and terminal stage

Significant enhanced expressions of aquaporin-1, -4 and -9 in the brains of various prion diseases

Serpin Signatures in Prion and Alzheimer’s Diseases

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