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ATG7 safeguards human neural integrity

Lookup NU author(s): Jack Collier, Dr Monika Olahova, Professor Robert Taylor

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Abstract

© 2021 Informa UK Limited, trading as Taylor & Francis Group. ATG7 drives macroautophagy, hereafter “autophagy”, by generating ATG12–ATG5 conjugates and lipidating Atg8 homologs including LC3. A pioneering body of work has defined the requirement of ATG7 for survival in mice and shown that neural-specific atg7 deletion causes neurodegeneration, but it has not been ascertained whether human life is compatible with ATG7 dysfunction. Recently, we defined the importance of ATG7 in human physiology by identifying twelve patients from five families harboring pathogenic, biallelic ATG7 variants causing a neurodevelopmental disorder. Patient fibroblasts show undetectable or severely diminished ATG7 protein levels, and biochemical assessment via autophagic flux and long-lived protein degradation assays demonstrated that attenuated autophagy underpins the pathology. Confirming the pathogenicity of patient variants, mouse cells expressing mutated ATG7 are unable to rescue LC3/Atg8 lipidation to wild-type levels. Our work defines mutated ATG7 as an important cause of human neurological disease and expands our understanding of autophagy in longevity and human health. We demonstrated that in certain circumstances, human survival with relatively mild phenotypes is possible even with undetectable levels of a nonredundant core autophagy protein.


Publication metadata

Author(s): Collier JJ, Olahova M, McWilliams TG, Taylor RW

Publication type: Article

Publication status: Published

Journal: Autophagy

Year: 2021

Pages: Epub ahead of print

Online publication date: 27/07/2021

Acceptance date: 05/07/2021

ISSN (print): 1554-8627

ISSN (electronic): 1554-8635

Publisher: Taylor and Francis Ltd

URL: https://doi.org/10.1080/15548627.2021.1953267

DOI: 10.1080/15548627.2021.1953267


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