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Use of a 2-aminothiazole to Treat Chronic Wasting Disease in Transgenic Mice.

ABSTRACT: Treatment with the 2-aminothiazole IND24 extended the survival of mice infected with mouse-adapted scrapie but also resulted in the emergence of a drug-resistant prion strain. Here, we determined whether IND24 extended the survival of transgenic mice infected with prions that caused scrapie in sheep or prions that caused chronic wasting disease (CWD; hereafter "CWD prions") in deer, using 2 isolates for each disease. IND24 doubled the incubation times for mice infected with CWD prions but had no effect on the survival of those infected with scrapie prions. Biochemical, neuropathologic, and cell culture analyses were used to characterize prion strain properties following treatment, and results indicated that the CWD prions were not altered by IND24, regardless of survival extension. These results suggest that IND24 may be a viable candidate for treating CWD in infected captive cervid populations and raise questions about why some prion strains develop drug resistance whereas others do not.

SUBMITTER: Berry D

PROVIDER: S-EPMC4551108 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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Use of a 2-aminothiazole to Treat Chronic Wasting Disease in Transgenic Mice.

Berry David D Giles Kurt K Oehler Abby A Bhardwaj Sumita S DeArmond Stephen J SJ Prusiner Stanley B SB

The Journal of infectious diseases 20150701

Treatment with the 2-aminothiazole IND24 extended the survival of mice infected with mouse-adapted scrapie but also resulted in the emergence of a drug-resistant prion strain. Here, we determined whether IND24 extended the survival of transgenic mice infected with prions that caused scrapie in sheep or prions that caused chronic wasting disease (CWD; hereafter "CWD prions") in deer, using 2 isolates for each disease. IND24 doubled the incubation times for mice infected with CWD prions but had no ...[more]

PMID: 26116725

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Project description:BackgroundChronic kidney disease (CKD) is commonly associated with cachexia, a condition that causes skeletal muscle wasting and an unfavourable prognosis. Although mechanisms leading to cachexia have been intensively studied, the advance of biological knowledges and technologies encourages us to make progress in understanding the pathogenesis of this disorder. Long noncoding RNAs (lncRNAs) are defined as >200 nucleotides RNAs but lack the protein-coding potential. LncRNAs are involved in the pathogenesis of many diseases, but whether they functionally involve in muscle protein loss has not been investigated.MethodsWe performed lncRNA array and identified an lncRNA, which we named Atrolnc-1, remarkably elevated in atrophying muscles from mice with cachexia. We examined how overexpression or knockdown of Atrolnc-1 could influence muscle protein synthesis and degradation. We also examined whether inhibition of Atrolnc-1 ameliorates muscle wasting in mice with CKD.ResultsWe documented that Atrolnc-1 expression is continuously increased in muscles of mice with fasting (5.4 fold), cancer (2.0 fold), or CKD (5.1 fold). We found that depressed insulin signalling stimulates the transcription factor C/EBP-α binding to the promoter of Atrolnc-1 and promotes the expression of Atrolnc-1. In cultured C2C12 myotubes, overexpression of Atrolnc-1 increases protein degradation (0.45±0.03 vs. 0.64±0.02, *p<0.05); Atrolnc-1 knockdown significantly reduces the rate of protein degradation stimulated by serum depletion (0.61±0.03 vs. 0.47±0.02, *p<0.05). Using mass spectrometry and a lncRNA pull-down assay, we identified that Atrolnc-1 interacts with A20 binding inhibitor of NF-κB-1 (ABIN-1). The interaction impairs function, resulting in enhanced NF-κB activity plus MuRF-1 transcription. This response is counteracted by CRISPR/dCas9 mediated overexpression. In muscles from normal mice, overexpression of Atrolnc-1 stimulates a 2.7-fold increase in MuRF-1 expression leading to myofibers atrophy. In contrast, Atrolnc-1 knockdown attenuates muscle wasting by 42% in mice with CKD via suppression of NF-κB activity and MuRF-1 expression.ConclusionsOur findings provide evidence that lncRNAs initiates the pathophysiological process of muscle wasting. The interaction between Atrolnc-1 and NF-κB signalling modulates muscle mass and proteolysis in CKD and perhaps other catabolic conditions.

Dataset Information

Use of a 2-aminothiazole to Treat Chronic Wasting Disease in Transgenic Mice.

Publications

Use of a 2-aminothiazole to Treat Chronic Wasting Disease in Transgenic Mice.

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