Mutation in ATG5 reduces autophagy and leads to ataxia with developmental delay
- University of Michigan, United States
- St Jude Children's Research Hospital, United States
- University of Michigan-Ann Arbor, United States
- St. Jude Children's Research Hospital, United States
- Boğaziçi University, Turkey
- Eötvös Loránd University, Hungary
- Istanbul University, Turkey
Abstract
Autophagy is required for the homeostasis of cellular material and is proposed to be involved in many aspects of health. Defects in the autophagy pathway have been observed in neurodegenerative disorders; however, no genetically-inherited pathogenic mutations in any of the core autophagy-related (ATG) genes have been reported in human patients to date. We identified a homozygous missense mutation, changing a conserved amino acid, in ATG5 in two siblings with congenital ataxia, mental retardation, and developmental delay. The subjects' cells display a decrease in autophagy flux and defects in conjugation of ATG12 to ATG5. The homologous mutation in yeast demonstrates a 30-50% reduction of induced autophagy. Flies in which Atg5 is substituted with the mutant human ATG5 exhibit severe movement disorder, in contrast to flies expressing the wild-type human protein. Our results demonstrate the critical role of autophagy in preventing neurological diseases and maintaining neuronal health.
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Human subjects: Study protocols including written informed consents have been approved by the University of Michigan Institutional Review Board and the Boğaziçi University Institutional Review Board for Research with Human Participants.
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© 2016, Kim et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Mutation in ATG5 reduces autophagy and leads to ataxia with developmental delay
eLife 5:e12245.
https://doi.org/10.7554/eLife.12245
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