ArticlePLoS genetics2015
A missense change in the ATG4D gene links aberrant autophagy to a neurodegenerative vacuolar storage disease.
Article in PLoS genetics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers, 1 of them a synthesis that pooled it.
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Who cites it
33 citing papers in PubMed, 1 synthesis or guideline pooled it, 54 citations in OpenAlex.
- Fabry disease cardiomyopathy: A state-of-the-art review.Progress in cardiovascular diseasesPooled it
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- An Overview of Canine Inherited Neurological Disorders with Known Causal Variants.Animals : an open access journal from MDPI · 2023Review
- Bi-allelic ATG4D variants are associated with a neurodevelopmental disorder characterized by speech and motor impairment.NPJ genomic medicine · 2023Article
- Cerebellar Abiotrophy in Australian Working Kelpies Is Associated with Two Major Risk Loci.Genes · 2022Article
- Monitoring basal autophagy in the retina utilizing CAG-mRFP-EGFP-MAP1LC3B reporter mouse: technical and biological considerations.Autophagy · 2022Article
- Cavin-1 promotes M2 macrophages/microglia polarization via SOCS3.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2022Article
- The spectrum of neurodevelopmental, neuromuscular and neurodegenerative disorders due to defective autophagy.Autophagy · 2022Article
- Subtractive CRISPR screen identifies the ATG16L1/vacuolar ATPase axis as required for non-canonical LC3 lipidation.Cell reports · 2021Article
- ATG4D is the main ATG8 delipidating enzyme in mammalian cells and protects against cerebellar neurodegeneration.Cell death and differentiation · 2021Article
- Non-canonical autophagy drives alternative ATG8 conjugation to phosphatidylserine.Molecular cell · 2021Article
- Autophagy in Drosophila and Zebrafish.Advances in experimental medicine and biology · 2021Article
- Altered Basal Autophagy Affects Extracellular Vesicle Release in Cells of Lagotto Romagnolo Dogs With a VariantVeterinary pathology · 2020Article
- Autophagy and disease: unanswered questions.Cell death and differentiation · 2020Review
- A comprehensive biomedical variant catalogue based on whole genome sequences of 582 dogs and eight wolves.Animal genetics · 2019Article
- Focal epilepsy with fear-related behavior as primary presentation in Boerboel dogs.Journal of veterinary internal medicine · 2019Article
Corrections and comments
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Authors and funding
23 authors at 9 institutions in 6 countries.
Funding
No grant is acknowledged in the PubMed record.
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.