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

Elife. 2016 Jan 26;5:e12245. doi: 10.7554/eLife.12245.

Myungjin Kim ¹, Erin Sandford ², Damian Gatica ³ ⁴, Yu Qiu ⁵, Xu Liu ³ ⁴, Yumei Zheng ⁵, Brenda A Schulman ⁵ ⁶, Jishu Xu ⁷, Ian Semple ¹, Seung-Hyun Ro ¹, Boyoung Kim ¹, R Nehir Mavioglu ⁸, Aslıhan Tolun ⁸, Andras Jipa ⁹ ¹⁰, Szabolcs Takats ¹⁰, Manuela Karpati ¹⁰, Jun Z Li ⁷ ¹¹, Zuhal Yapici ¹², Gabor Juhasz ⁹ ¹⁰, Jun Hee Lee ¹, Daniel J Klionsky ³ ⁴, Margit Burmeister ² ⁷ ¹¹ ¹³

Affiliations

1 Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States.
2 Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, United States.
3 Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, United States.
4 Life Sciences Institute, University of Michigan, Ann Arbor, United States.
5 Department of Structural Biology, St Jude Children's Research Hospital, Memphis, United States.
6 Howard Hughes Medical Institute, St. Jude Children's Research Hospital, Memphis, United States.
7 Department of Human Genetics, University of Michigan, Ann Arbor, United States.
8 Department of Molecular Biology and Genetics, Boğaziçi University, Istanbul, Turkey.
9 Institute of Genetics, Biological Research Centre, Hungarian Academy of Sciences, Szeged, Hungary.
10 Department of Anatomy, Cell and Developmental Biology, Eötvös Loránd University, Budapest, Hungary.
11 Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, United States.
12 Department of Neurology, Faculty of Medicine, Istanbul University, Istanbul, Turkey.
13 Department of Psychiatry, University of Michigan, Ann Arbor, United States.

PMID: 26812546 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.

Keywords

d. melanogaster; s. cerevisiae; ataxia; autophagy; human; human biology; medicine; neuroscience; next generation sequencing.

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