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

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Neurodegenerative disorders affect millions of people worldwide. We describe a novel neurodegenerative disease in a canine model, characterized by progressive cerebellar ataxia and cellular vacuolization. Our genetic analyses identified a single nucleotide change in the autophagy-related ATG4D gene in affected dogs. The ATG4D gene has not been linked to inherited diseases before. The autophagy-lysosome pathway plays an important role in degrading and recycling different cellular components. Disturbed autophagy has been reported in several different diseases but mutations in core autophagy components are rare. Histological analyses of affected canine brain tissues revealed altered autophagic flux, and a knockdown of the gene in the zebrafish model caused marked neurodevelopmental alterations and neurodegeneration. Our findings identify a new disease-causing pathway and implicate the ATG4D protease as an important mediator for neuronal homeostasis. Furthermore, our study establishes a large animal model to investigate the role of ATG4D in autophagy and to test possible treatment options.

Vyšlo v časopise: A Missense Change in the Gene Links Aberrant Autophagy to a Neurodegenerative Vacuolar Storage Disease. PLoS Genet 11(4): e32767. doi:10.1371/journal.pgen.1005169
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1005169

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