Impairment of autophagy in scrapie-infected transgenic mice at the clinical stage

López-Pérez, Óscar ; Toivonen, Janne Markus (Universidad de Zaragoza) ; Otero, Alicia (Universidad de Zaragoza) ; Solanas, Laura ; Zaragoza, Pilar (Universidad de Zaragoza) ; Badiola, Juan José (Universidad de Zaragoza) ; Osta, Rosario (Universidad de Zaragoza) ; Bolea, Rosa (Universidad de Zaragoza) ; Martín-Burriel, Inmaculada (Universidad de Zaragoza)
Impairment of autophagy in scrapie-infected transgenic mice at the clinical stage
Resumen: 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.

Idioma: Inglés
DOI: 10.1038/s41374-019-0312-z
Año: 2020
Publicado en: LABORATORY INVESTIGATION 100, 1 (2020), 52-63
ISSN: 0023-6837

Factor impacto JCR: 5.662 (2020)
Categ. JCR: PATHOLOGY rank: 11 / 77 = 0.143 (2020) - Q1 - T1
Categ. JCR: MEDICINE, RESEARCH & EXPERIMENTAL rank: 38 / 140 = 0.271 (2020) - Q2 - T1

Factor impacto SCIMAGO: 1.542 - Cell Biology (Q1) - Pathology and Forensic Medicine (Q1) - Molecular Biology (Q1)

Financiación: info:eu-repo/grantAgreement/ES/DGA/A19-17R
Financiación: info:eu-repo/grantAgreement/ES/DGA/C012-2014
Financiación: info:eu-repo/grantAgreement/ES/DGA/C020-2014
Financiación: info:eu-repo/grantAgreement/ES/FIS/PI17-00949
Financiación: info:eu-repo/grantAgreement/ES/MINECO/AGL2015-67945-P
Tipo y forma: Article (PostPrint)
Área (Departamento): Área Genética (Dpto. Anatom.,Embri.Genét.Ani.)
Área (Departamento): Área Sanidad Animal (Dpto. Patología Animal)

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 Record created 2020-03-24, last modified 2022-02-08

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