Basal Autophagy is altered in Lagotto Romagnolo Dogs with an ATG4D mutation

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Syrjä , P , Anwar , T , Pääkkönen , T , Kyöstilä , K , Hultin Jäderlund , K , Cozzi , F , Rohdin , C , Hahn , K , Wohlsein , P , Baumgärtner , W , Henke , D , Oevermann , A , Sukura , A , Leeb , T , Lohi , H & Eskelinen , E-L 2017 , ' Basal Autophagy is altered in Lagotto Romagnolo Dogs with an ATG4D mutation ' , Veterinary Pathology , vol. 54 , no. 6 , pp. 953-963 . https://doi.org/10.1177/0300985817712793

Title: Basal Autophagy is altered in Lagotto Romagnolo Dogs with an ATG4D mutation
Author: Syrjä, Pernilla; Anwar, Tahira; Pääkkönen, Tarja; Kyöstilä, Kaisa; Hultin Jäderlund, Karin; Cozzi, Francesca; Rohdin, Cecilia; Hahn, Kerstin; Wohlsein, Peter; Baumgärtner, Wolfgang; Henke, Diana; Oevermann, Anna; Sukura, Antti; Leeb, Tosso; Lohi, Hannes; Eskelinen, Eeva-Liisa
Contributor: University of Helsinki, Departments of Faculty of Veterinary Medicine
University of Helsinki, Biosciences
University of Helsinki, Equine and Small Animal Medicine
University of Helsinki, Research Programs Unit
University of Helsinki, Departments of Faculty of Veterinary Medicine
University of Helsinki, Medicum
University of Helsinki, Biosciences
Date: 2017-11
Language: eng
Number of pages: 11
Belongs to series: Veterinary Pathology
ISSN: 0300-9858
URI: http://hdl.handle.net/10138/297783
Abstract: A missense variant in the autophagy-related ATG4D-gene has been associated with a progressive degenerative neurological disease in Lagotto Romagnolo (LR) dogs. In addition to neural lesions, affected dogs show an extraneural histopathological phenotype characterized by severe cytoplasmic vacuolization, a finding not previously linked with disturbed autophagy in animals. Here we aimed at testing the hypothesis that autophagy is altered in the affected dogs, at reporting the histopathology of extraneural tissues and at excluding lysosomal storage diseases. Basal and starvation-induced autophagy were monitored by Western blotting and immunofluorescence of microtubule associated protein 1A/B light chain3 (LC3) in fibroblasts from 2 affected dogs. The extraneural findings of 9 euthanized LRs and skin biopsies from 4 living affected LRs were examined by light microscopy, electron microscopy, and immunohistochemistry (IHC), using antibodies against autophagosomal membranes (LC3), autophagic cargo (p62), and lysosomal membranes (LAMP2). Biochemical screening of urine and fibroblasts of 2 affected dogs was performed. Under basal conditions, the affected fibroblasts contained significantly more LC3-II and LC3-positive vesicles than did the controls. Morphologically, several cells, including serous secretory epithelium, endothelial cells, pericytes, plasma cells, and macrophages, contained cytoplasmic vacuoles with an ultrastructure resembling enlarged amphisomes, endosomes, or multivesicular bodies. IHC showed strong membranous LAMP2 positivity only in sweat glands. The results show that basal but not induced autophagy is altered in affected fibroblasts. The ultrastructure of affected cells is compatible with altered autophagic and endo-lysosomal vesicular traffic. The findings in this spontaneous disease provide insight into possible tissue-specific roles of basal autophagy.
Subject: 413 Veterinary science
1182 Biochemistry, cell and molecular biology
basal au tophagy
Western blot
immunofluorescence
electron microscopy
cytoplasmic vacuolization
pathology
ATG4D
dog
LYSOSOMAL STORAGE DISEASES
CELLS
MUCOPOLYSACCHARIDOSES
DEGRADATION
ACTIVATION
MATURATION
CLEARANCE
PROTEIN
FLUX
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