88303 20240104111814.0 doi 10.1038/s41374-019-0312-z sideral 113135 ART-2020-113135 eng López-Pérez, Óscar (orcid)0000-0003-2454-2114 Impairment of autophagy in scrapie-infected transgenic mice at the clinical stage 2020 Access copy available to the general public Unrestricted Autophagy appears to play a role in the etiology and progress of misfolded protein disorders. Although this process is dysregulated in prion diseases, it is unknown whether this impairment is a cause or a consequence of prion neuropathology. The study of autophagy during the progress of the disease could elucidate its role. For this purpose, we have investigated its regulation at different stages of the disease in Tg338 mice, a transgenic murine model that overexpresses the highly susceptible ovine VRQ prion protein allele. Mice were intracerebrally inoculated with mouse adapted classical scrapie and euthanized at the preclinical and clinical stages of the disease. Regulation of autophagy was investigated analyzing the distribution of LC3-B and p62 proteins by immunohistochemistry. Moreover, the expression of genes involved in autophagy regulation was quantified by real-time PCR. LC3-B and p62 proteins were downregulated and upregulated, respectively, in the central nervous system of infected mice with clinical signs of scrapie. Accumulation of p62 correlated with scrapierelated lesions, suggesting an impairment of autophagy in highly prion-affected areas. In addition, Gas5 (growth arrestspecific 5), Atg5 (autophagy-related 5), and Fbxw7 (F-box and WD repeat domain containing 7) transcripts were downregulated in mesencephalon and cervical spinal cord of the same group of animals. The impairment of autophagic machinery seems to be part of the pathological process of scrapie, but only during the late stage of prion infection. Similarities between Tg338 mice and the natural ovine disease make them a reliable in vivo model to study prion infection and autophagy side by side. info:eu-repo/grantAgreement/ES/DGA/A19-17R info:eu-repo/grantAgreement/ES/DGA/C012-2014 info:eu-repo/grantAgreement/ES/DGA/C020-2014 info:eu-repo/grantAgreement/ES/FIS/PI17-00949 info:eu-repo/grantAgreement/ES/MINECO/AGL2015-67945-P info:eu-repo/semantics/openAccess All rights reserved http://www.europeana.eu/rights/rr-f/ 5.662 2020 PATHOLOGY 11 / 77 = 0.143 2020 Q1 T1 MEDICINE, RESEARCH & EXPERIMENTAL 38 / 140 = 0.271 2020 Q2 T1 1.542 2020 Cell Biology 2020 Q1 Pathology and Forensic Medicine 2020 Q1 Molecular Biology 2020 Q1 info:eu-repo/semantics/article info:eu-repo/semantics/acceptedVersion Toivonen, Janne Markus Universidad de Zaragoza (orcid)0000-0002-7243-1737 Otero, Alicia Universidad de Zaragoza (orcid)0000-0001-9075-2764 Solanas, Laura Zaragoza, Pilar Universidad de Zaragoza (orcid)0000-0001-5740-0185 Badiola, Juan José Universidad de Zaragoza (orcid)0000-0002-7173-7216 Osta, Rosario Universidad de Zaragoza (orcid)0000-0001-5687-6704 Bolea, Rosa Universidad de Zaragoza (orcid)0000-0002-2746-3932 Martín-Burriel, Inmaculada Universidad de Zaragoza (orcid)0000-0001-6016-4726 1001 420 Universidad de Zaragoza Dpto. Anatom.,Embri.Genét.Ani. Área Genética 1009 773 Universidad de Zaragoza Dpto. Patología Animal Área Sanidad Animal 100, 1 (2020), 52-63 Lab. invest. LABORATORY INVESTIGATION 0023-6837 5173212 http://zaguan.unizar.es/record/88303/files/texto_completo.pdf Postprint 161155 http://zaguan.unizar.es/record/88303/files/texto_completo.jpg?subformat=icon icon Postprint oai:zaguan.unizar.es:88303 articulos driver 2024-01-04-11:03:55 ARTICLE