Mutation in ATG5 reduces autophagy and leads to ataxia with developmental delay

Authors

Myungjin Kim, University of Michigan-Ann Arbor
Erin Sandford, University of Michigan-Ann Arbor
Damian Gatica, University of Michigan-Ann Arbor
Yu Qiu, St. Jude Children's Research Hospital
Xu Liu, University of Michigan-Ann Arbor
Yumei Zheng, St. Jude Children's Research Hospital
Brenda A. Schulman, St. Jude Children's Research Hospital
Jishu Xu, University of Michigan-Ann Arbor
Ian Semple, University of Michigan-Ann Arbor
Seung-Hyun Ro, University of Michigan-Ann ArborFollow
Boyoung Kim, University of Michigan-Ann Arbor
R. Nehir Mavioglu, Bogazici University
Aslihan Tolun, Bogazici University
Andras Jipa, Hungarian Academy of Sciences
Szabolcs Takats, Eotvos Lorand University
Manuela Karpati, Eotvos Lorand University
Jun Z. Li, University of Michigan-Ann Arbor
Zuhal Yapici, Istanbul University
Gabor Juhasz, Hungarian Academy of Sciences
Jun Hee Lee, University of Michigan-Ann ArborFollow
Daniel J. Klionsky, University of Michigan-Ann ArborFollow
Margit Burmeister, University of Michigan-Ann ArborFollow

Document Type

Article

Date of this Version

2016

Citation

eLife 2016;5:e12245.

Comments

Copyright Kim et al.

Open access

DOI: 10.7554/eLife.12245

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.