A Missense Change in the ATG4D Gene Links Aberrant Autophagy to a Neurodegenerative Vacuolar Storage Disease

• DOI: 10.1371/journal.pgen.1005169
• Publication Date: 2015-04-15T19:29:24Z
• Authors: Kaisa Kyöstilä; Pernilla Syrjä; Vidhya Jagannathan; Gayathri Chandras...; Tarja S. Jokinen; Eija H. Seppälä; Doreen Becker; Michaela Drögemüller; Elisabeth Dietschi; Cord Drögemüller; Johann Lang; Frank Steffen; Cecilia Rohdin; Karin H. Jäderlund; Anu K. Lappalainen; Kerstin Hahn; Peter Wohlsein; Wolfgang Baumgärtner; Diana Henke; Anna Oevermann; Juha Kere; Hannes Lohi; Tosso Leeb
• Keywords: 0301 basic medicine; Molecular Sequence Data; Mutation, Missense; PROTEIN; 610 Medicine & health; UBIQUITIN-PROTEASOME SYSTEM; QH426-470; CASPASE CLEAVAGE; 03 medical and health sciences; Dogs; QUALITY-CONTROL; Genetics; Autophagy; Animals; Amino Acid Sequence; Zebrafish; 630 Agriculture; Base Sequence; Brain; Neurodegenerative Diseases; DEGENERATION; DEGRADATION; NERVOUS-SYSTEM; FAMILY; 3. Good health; GENOME; MICE; Biomedicine; Cysteine Endopeptidases; Vacuoles; 570 Life sciences; biology; 590 Animals (Zoology); Research Article

Inherited neurodegenerative disorders are debilitating diseases that occur across different species. We have performed clinical, pathological and genetic studies to characterize a novel canine disease present in the Lagotto Romagnolo dog breed. Affected dogs suffer from progressive cerebellar ataxia, sometimes accompanied by episodic nystagmus behavioral changes. Histological examination revealed unique changes, including profound neuronal cytoplasmic vacuolization nervous system, as well spheroid formation aggregation of vacuoles secretory epithelial tissues mesenchymal cells. Genetic analyses uncovered missense change, c.1288G>A; p.A430T, autophagy-related ATG4D gene on chromosome 20 with highly significant association (p = 3.8 x 10-136) cohort more than 2300 dogs. encodes poorly characterized cysteine protease belonging macroautophagy pathway. Accordingly, our histological indicated altered autophagic flux affected tissues. The knockdown zebrafish homologue atg4da resulted widespread developmental disturbance neurodegeneration central system. Our study describes previously unknown neurological particular features implicates protein an important autophagy mediator homeostasis. phenotype serves model delineate disease-causing mechanism(s) function, can also be used explore treatment options. Furthermore, results reveal candidate for human enable development test veterinary diagnostic breeding purposes.