title: A missense change in the ATG4D gene links aberrant autophagy to a neurodegenerative vacuolar storage disease.
abstract: Inherited neurodegenerative disorders are debilitating diseases that occur across different species. We have performed clinical, pathological and genetic studies to characterize a novel canine neurodegenerative disease present in the Lagotto Romagnolo dog breed. Affected dogs suffer from progressive cerebellar ataxia, sometimes accompanied by episodic nystagmus and behavioral changes. Histological examination revealed unique pathological changes, including profound neuronal cytoplasmic vacuolization in the nervous system, as well as spheroid formation and cytoplasmic aggregation of vacuoles in secretory epithelial tissues and mesenchymal cells. Genetic analyses uncovered a missense change, c.1288G>A; p.A430T, in the autophagy-related ATG4D gene on canine chromosome 20 with a highly significant disease association (p = 3.8 x 10-136) in a cohort of more than 2300 Lagotto Romagnolo dogs. ATG4D encodes a poorly characterized cysteine protease belonging to the macroautophagy pathway. Accordingly, our histological analyses indicated altered autophagic flux in affected tissues. The knockdown of the zebrafish homologue atg4da resulted in a widespread developmental disturbance and neurodegeneration in the central nervous system. Our study describes a previously unknown canine neurological disease with particular pathological features and implicates the ATG4D protein as an important autophagy mediator in neuronal homeostasis. The canine phenotype serves as a model to delineate the disease-causing pathological mechanism(s) and ATG4D function, and can also be used to explore treatment options. Furthermore, our results reveal a novel candidate gene for human neurodegeneration and enable the development of a genetic test for veterinary diagnostic and breeding purposes.
authors: Department of Veterinary Biosciences, University of Helsinki, Helsinki, Finland; Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland; Department of Molecular Genetics, Folkhälsan Institute of Genetics, Helsinki, Finland.
authors: Kaisa
authors: K
authors: Kyöstilä
authors: Department of Veterinary Biosciences, University of Helsinki, Helsinki, Finland.
authors: Pernilla
authors: P
authors: Syrjä
authors: Institute of Genetics, Vetsuisse Faculty, University of Bern, Bern, Switzerland.
authors: Vidhya
authors: V
authors: Jagannathan
authors: Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.
authors: Gayathri
authors: G
authors: Chandrasekar
authors: Department of Equine and Small Animal Medicine, University of Helsinki, Helsinki, Finland.
authors: Tarja S
authors: TS
authors: Jokinen
authors: Department of Veterinary Biosciences, University of Helsinki, Helsinki, Finland; Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland; Department of Molecular Genetics, Folkhälsan Institute of Genetics, Helsinki, Finland.
authors: Eija H
authors: EH
authors: Seppälä
authors: Institute of Genetics, Vetsuisse Faculty, University of Bern, Bern, Switzerland.
authors: Doreen
authors: D
authors: Becker
authors: Institute of Genetics, Vetsuisse Faculty, University of Bern, Bern, Switzerland.
authors: Michaela
authors: M
authors: Drögemüller
authors: Institute of Genetics, Vetsuisse Faculty, University of Bern, Bern, Switzerland.
authors: Elisabeth
authors: E
authors: Dietschi
authors: Institute of Genetics, Vetsuisse Faculty, University of Bern, Bern, Switzerland.
authors: Cord
authors: C
authors: Drögemüller
authors: Department of Clinical Veterinary Medicine, Division of Clinical Radiology, Vetsuisse Faculty, University of Bern, Bern, Switzerland.
authors: Johann
authors: J
authors: Lang
authors: Neurology Service, Department of Small Animals, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland.
authors: Frank
authors: F
authors: Steffen
authors: University Animal Hospital, Swedish University of Agricultural Sciences, Uppsala, Sweden.
authors: Cecilia
authors: C
authors: Rohdin
authors: Department of Companion Animal Clinical Sciences, Norwegian University of Life Sciences, Oslo, Norway.
authors: Karin H
authors: KH
authors: Jäderlund
authors: Department of Equine and Small Animal Medicine, University of Helsinki, Helsinki, Finland.
authors: Anu K
authors: AK
authors: Lappalainen
authors: Department of Pathology, University of Veterinary Medicine Hannover, Hannover, Germany.
authors: Kerstin
authors: K
authors: Hahn
authors: Department of Pathology, University of Veterinary Medicine Hannover, Hannover, Germany.
authors: Peter
authors: P
authors: Wohlsein
authors: Department of Pathology, University of Veterinary Medicine Hannover, Hannover, Germany.
authors: Wolfgang
authors: W
authors: Baumgärtner
authors: Division of Neurological Sciences, Vetsuisse Faculty, University of Bern, Bern, Switzerland.
authors: Diana
authors: D
authors: Henke
authors: Division of Neurological Sciences, Vetsuisse Faculty, University of Bern, Bern, Switzerland.
authors: Anna
authors: A
authors: Oevermann
authors: Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland; Department of Molecular Genetics, Folkhälsan Institute of Genetics, Helsinki, Finland; Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden; Science for Life Laboratory, Karolinska Institutet, Solna, Sweden.
authors: Juha
authors: J
authors: Kere
authors: Department of Veterinary Biosciences, University of Helsinki, Helsinki, Finland; Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland; Department of Molecular Genetics, Folkhälsan Institute of Genetics, Helsinki, Finland.
authors: Hannes
authors: H
authors: Lohi
authors: Institute of Genetics, Vetsuisse Faculty, University of Bern, Bern, Switzerland.
authors: Tosso
authors: T
authors: Leeb
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001343:Autophagy / Q000235:genetics*; D001483:Base Sequence; D001921:Brain / Q000378:metabolism / Q000473:pathology; D003546:Cysteine Endopeptidases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D004285:Dogs; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D019636:Neurodegenerative Diseases / Q000235:genetics* / Q000473:pathology / Q000662:veterinary; D014617:Vacuoles / Q000235:genetics / Q000378:metabolism*; D015027:Zebrafish
chemical_list: D003546:Cysteine Endopeptidases