Format

Send to

Choose Destination
PLoS Genet. 2015 Apr 15;11(4):e1005169. doi: 10.1371/journal.pgen.1005169. eCollection 2015 Apr.

A missense change in the ATG4D gene links aberrant autophagy to a neurodegenerative vacuolar storage disease.

Author information

1
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.
2
Department of Veterinary Biosciences, University of Helsinki, Helsinki, Finland.
3
Institute of Genetics, Vetsuisse Faculty, University of Bern, Bern, Switzerland.
4
Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.
5
Department of Equine and Small Animal Medicine, University of Helsinki, Helsinki, Finland.
6
Department of Clinical Veterinary Medicine, Division of Clinical Radiology, Vetsuisse Faculty, University of Bern, Bern, Switzerland.
7
Neurology Service, Department of Small Animals, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland.
8
University Animal Hospital, Swedish University of Agricultural Sciences, Uppsala, Sweden.
9
Department of Companion Animal Clinical Sciences, Norwegian University of Life Sciences, Oslo, Norway.
10
Department of Pathology, University of Veterinary Medicine Hannover, Hannover, Germany.
11
Division of Neurological Sciences, Vetsuisse Faculty, University of Bern, Bern, Switzerland.
12
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.

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.

PMID:
25875846
PMCID:
PMC4398399
DOI:
10.1371/journal.pgen.1005169
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Public Library of Science Icon for PubMed Central
Loading ...
Support Center