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

Journal Article · · eLife
DOI:https://doi.org/10.7554/eLife.12245· OSTI ID:1241073
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  1. Univ. of Michigan, Ann Arbor, MI (United States)
  2. St. Jude Children's Research Hospital, Memphis, TN (United States)
  3. Bogazici Univ., Istanbul (Turkey)
  4. Hungarian Academy of Sciences, Szeged (Hungary); Eotvos Lorand Univ. Budapest (Hungary)
  5. Eotvos Lorand Univ., Budapest (Hungary)
  6. Istanbul Univ. (Turkey)
+ Show Author Affiliations

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.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Organization:
National Institutes of Health (NIH); American Heart Assoc.; Bogazic ̧Univ. Research Fund; Wellcome Trust; Lendulet; American Lebanese Syrian Assoc. Charities/St. Jude; Howard Hughes Medical Inst.; Magyar Tudomanyos Akademia
Grant/Contract Number:
R01-NS078560; R21-OD018265; R01-GM077053; R01-GM053396; 14POST19890021; 6655; 087518/Z/08/Z; LP2014-2
OSTI ID:
1241073
Journal Information:
eLife, Vol. 5, Issue 2016; ISSN 2050-084X
Publisher:
eLife Sciences Publications, Ltd.Copyright Statement
Country of Publication:
United States
Language:
ENGLISH
Citation Metrics:
Cited by: 134 works
Citation information provided by
Web of Science

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Cited By (28)

Mutations in VPS13D lead to a new recessive ataxia with spasticity and mitochondrial defects journal May 2018
Compartment-specific dynamics and functions of autophagy in neurons: Dynamics and Functions of Neuronal Autophagy journal December 2017
Novel insights into the clinical and molecular spectrum of congenital disorders of autophagy journal April 2019
Autophagy core machinery: overcoming spatial barriers in neurons journal August 2016
Consensus Paper. Cerebellar Reserve: From Cerebellar Physiology to Cerebellar Disorders journal December 2019
Molecular Targets and Therapeutic Strategies in Spinocerebellar Ataxia Type 7 journal August 2019
Drosophila Atg9 regulates the actin cytoskeleton via interactions with profilin and Ena journal November 2019
Autophagy and disease: unanswered questions journal January 2020
A brief history of autophagy from cell biology to physiology and disease journal April 2018
Autophagy as a promoter of longevity: insights from model organisms journal July 2018
Functional Transcriptome Analysis in ARSACS KO Cell Model Reveals a Role of Sacsin in Autophagy journal August 2019
Autophagy in the mammalian nervous system: a primer for neuroscientists journal September 2019
Autophagy wins the 2016 Nobel Prize in Physiology or Medicine: Breakthroughs in baker's yeast fuel advances in biomedical research journal December 2016
The proteasome regulator PI31 is required for protein homeostasis, synapse maintenance, and neuronal survival in mice journal November 2019
The lysosomal membrane protein LAMP2A promotes autophagic flux and prevents SNCA-induced Parkinson disease-like symptoms in the Drosophila brain journal August 2018
An Amish founder mutation disrupts a PI(3)P-WHAMM-Arp2/3 complex–driven autophagosomal remodeling pathway journal September 2017
Vps13D is required for mitochondrial fission and mitophagy triggered by fission defects in Drosophila neurons journal December 2020
Autophagy in childhood neurological disorders journal November 2018
Targeting Alzheimer's disease with gene and cell therapies journal June 2018
Using Drosophila Models of Amyloid Toxicity to Study Autophagy in the Pathogenesis of Alzheimer’s Disease journal January 2018
Drosophila Atg16 promotes enteroendocrine cell differentiation via regulation of intestinal Slit/Robo signaling journal October 2017
Exploring Autophagy in Drosophila journal July 2017
Glutamine Synthetase 1 Increases Autophagy Lysosomal Degradation of Mutant Huntingtin Aggregates in Neurons, Ameliorating Motility in a Drosophila Model for Huntington’s Disease journal January 2020
Autophagy linked FYVE (Alfy/WDFY3) is required for establishing neuronal connectivity in the mammalian brain journal September 2016
The proteasome regulator PI31 is required for protein homeostasis, synapse maintenance and neuronal survival in mice journal July 2019
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