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 organization: Departments of Faculty of Veterinary Medicine
Veterinary Biosciences
Veterinary Pathology and Parasitology
Antti Sukura / Principal Investigator
University of Helsinki
Biosciences
Autophagy
Equine and Small Animal Medicine
Research Programs Unit
Hannes Tapani Lohi / Principal Investigator
Research Programme for Molecular Neurology
Medicum
Veterinary Genetics
Department of Medical and Clinical Genetics
Biochemistry and Biotechnology
Date: 2017-11
Language: eng
Number of pages: 11
Belongs to series: Veterinary Pathology
ISSN: 0300-9858
DOI: https://doi.org/10.1177/0300985817712793
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
Peer reviewed: Yes
Usage restriction: openAccess
Self-archived version: publishedVersion
Funder: European Union
Acedemy of Finland
Grant number:


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