Chapter Thirteen - Genetic defects of autophagy linked to disease

https://doi.org/10.1016/bs.pmbts.2020.04.001Get rights and content

Abstract

Autophagy is a highly conserved lysosomal degradation pathway responsible for rapid elimination of unwanted cytoplasmic materials in response to stressful conditions. This cytoprotective function is essential for maintenance of cellular homeostasis and is mediated by conserved autophagy-related genes (ATG) and autophagic receptors. Impairment of autophagy frequently results in a wide variety of human pathologies. Recent studies have revealed direct links between diverse diseases and genetic defects of core autophagy genes, autophagy-associated genes, and genes encoding autophagic receptors. Here we provide a general description of autophagy-related genes and their mutations or polymorphisms that play a causative role in specific human disorders or may be risk factors for them.

Section snippets

Autophagy as a mechanism for intracellular homeostasis

Autophagy is a tightly regulated catabolic process that facilitates lysosomal degradation of unwanted cellular components including damage organelles, long-lived or aggregative proteins, and invasive microorganisms.1, 2 The autophagic pathway is essential for the maintenance of cellular homeostasis. The process is initiated by nucleation of an isolation membrane, which elongates into a cup-shaped phagophore that sequestrates cytoplasmic components and then closes on itself, sealing the contents

Diseases caused by genetic mutations in core ATG genes

Wide-ranging studies over the past two decades have established links between aberrant autophagy and various diseases.1 Dysfunctional autophagy due to genetic aberrations or even polymorphism (mostly identified by genome-wide association studies; GWAS) in conserved core autophagy-related genes (ATG) have been implicated in muscular, inflammatory, metabolic, neurodegenerative and immune system diseases, as well as in cancer.28 Importantly, ATG5−/− and ATG7−/− (conditional knockout) mice exhibit

Disease caused by mutations in genes associated with autophagy

Autophagic impairments leading to various human disorders may occur not only because of mutations in genes encoding the core autophagic machinery proteins, but also as a result of mutations or polymorphisms in genes encoding proteins associated with autophagic functions such as fusion between lysosomes and autophagosomes, lysosomal regeneration after cargo degradation, cargo targeting, or scaffolding for phagophore biogenesis. In this section we focus, in alphabetic order, on

Diseases caused by mutations in autophagic receptor genes

Selective autophagy is mediated by various autophagic receptors, including p62, OPTN, NDP52 and more, which lead to exclusive degradation of cargo following its specific recognition and sequestration into autophagosomes through binding to ATG8 family members in an ubiquitin-dependent and -independent manner.26 Mutations in autophagy receptor genes are strongly linked to a wide range of human diseases, especially neurodegenerative and inflammatory disorders. In this section we focus, in

Conclusions

This chapter records a diverse list of pathologies that are caused by mutations in human core autophagy genes, in genes associated with autophagy, and in genes encoding autophagic receptors. Since most of these genes function not only in autophagy but also in other biological pathways, a large spectrum of mutations has been implicated in the pathogenesis of human diseases. Notably, most of known genetic aberrations in autophagy result in neurological or inflammatory disorders. Since autophagy

Acknowledgments

Z.E. is the incumbent of the Harold L. Korda Professorial Chair of Biology and is supported by the Jeanne and Joseph Nissim Center for Life Sciences Research, and the Estate of Emile Mimran. We are grateful for funding from the Israel Science Foundation ISF (Grant #215/19), the Legacy Heritage Fund (Grant #1935/16), the Sagol Longevity Foundation, and the Yeda-Sela Center for Basic Research. We apologize to those authors whose works could not be cited here because of the journal's restriction

References (167)

  • A. Tschentscher et al.

    Analysis of the C19orf12 and WDR45 genes in patients with neurodegeneration with brain iron accumulation

    J Neurol Sci

    (2015)
  • S. Hoffjan et al.

    WDR45 mutations in Rett (-like) syndrome and developmental delay: case report and an appraisal of the literature

    Mol Cell Probes

    (2016)
  • K. Fujihara

    Neuromyelitis optica and astrocytic damage in its pathogenesis

    J Neurol Sci

    (2011)
  • R. Meas et al.

    DNA repair and systemic lupus erythematosus

    DNA Repair (Amst)

    (2017)
  • R. Gualtierotti et al.

    Updating on the pathogenesis of systemic lupus erythematosus

    Autoimmun Rev

    (2010)
  • Y. Li et al.

    Novel and functional ATG12 gene variants in sporadic Parkinson's disease

    Neurosci Lett

    (2017)
  • R.B. Sartor

    Microbial influences in inflammatory bowel diseases

    Gastroenterology

    (2008)
  • C.Z. Chen et al.

    Association of Egr-1 and autophagy-related gene polymorphism in men with chronic obstructive pulmonary disease

    J Formos Med Assoc

    (2015)
  • Y. Ohsumi et al.

    Two ubiquitin-like conjugation systems essential for autophagy

    Semin Cell Dev Biol

    (2004)
  • D. Chen et al.

    Genetic analysis of the ATG7 gene promoter in sporadic Parkinson's disease

    Neurosci Lett

    (2013)
  • M. Li et al.

    Kinetics comparisons of mammalian Atg4 homologues indicate selective preferences toward diverse Atg8 substrates

    J Biol Chem

    (2011)
  • C. Wu et al.

    Genetic association, mRNA and protein expression analysis identify ATG4C as a susceptibility gene for Kashin-Beck disease

    Osteoarthr Cartil

    (2017)
  • J. Xu et al.

    Identification of a novel 21bp-insertion variant within the LC3B gene promoter in sporadic Parkinson's disease

    Transl Res

    (2013)
  • Y. Tian et al.

    C. elegans screen identifies autophagy genes specific to multicellular organisms

    Cell

    (2010)
  • J.P. Vonsattel et al.

    Huntington's disease—neuropathology

    Handb Clin Neurol

    (2011)
  • K.R. Croce et al.

    A role for autophagy in Huntington's disease

    Neurobiol Dis

    (2019)
  • S. Chauhan et al.

    IRGM governs the core autophagy machinery to conduct antimicrobial defense

    Mol Cell

    (2015)
  • I. Dikic et al.

    Mechanism and medical implications of mammalian autophagy

    Nat Rev Mol Cell Biol

    (2018)
  • W. Xie et al.

    Aberrant regulation of autophagy in mammalian diseases

    Biol Lett

    (2018)
  • N. van Beek et al.

    Genetic aberrations in macroautophagy genes leading to diseases

    Biochim Biophys Acta Mol Cell Res

    (1865)
  • S.A. Tooze et al.

    Endocytosis and autophagy: exploitation or cooperation?

    Cold Spring Harb Perspect Biol

    (2014)
  • J. Ramesh et al.

    Autophagy intertwines with different diseases-recent strategies for therapeutic approaches

    Diseases

    (2019)
  • C. He et al.

    Regulation mechanisms and signaling pathways of autophagy

    Annu Rev Genet

    (2009)
  • P. Jiang et al.

    Autophagy and human diseases

    Cell Res

    (2014)
  • N. Mizushima et al.

    Autophagy in mammalian development and differentiation

    Nat Cell Biol

    (2010)
  • C.A. Lamb et al.

    The autophagosome: origins unknown, biogenesis complex

    Nat Rev Mol Cell Biol

    (2013)
  • J. Bestebroer et al.

    Hidden behind autophagy: the unconventional roles of ATG proteins

    Traffic

    (2013)
  • S. Chowdhury et al.

    Insights into autophagosome biogenesis from structural and biochemical analyses of the ATG2A-WIPI4 complex

    Proc Natl Acad Sci USA

    (2018)
  • R. Gomez-Sanchez et al.

    Atg9 establishes Atg2-dependent contact sites between the endoplasmic reticulum and phagophores

    J Cell Biol

    (2018)
  • H. Cheong et al.

    Ammonia-induced autophagy is independent of ULK1/ULK2 kinases

    Proc Natl Acad Sci USA

    (2011)
  • Y. Grishchuk et al.

    Beclin 1-independent autophagy contributes to apoptosis in cortical neurons

    Autophagy

    (2011)
  • X.J. Zhou et al.

    Genetic association of PRDM1-ATG5 intergenic region and autophagy with systemic lupus erythematosus in a Chinese population

    Ann Rheum Dis

    (2011)
  • I. Nemazanyy et al.

    Defects of Vps15 in skeletal muscles lead to autophagic vacuolar myopathy and lysosomal disease

    EMBO Mol Med

    (2013)
  • Y. Nishida et al.

    Discovery of Atg5/Atg7-independent alternative macroautophagy

    Nature

    (2009)
  • M.A. Sanjuan et al.

    Toll-like receptor signalling in macrophages links the autophagy pathway to phagocytosis

    Nature

    (2007)
  • M.A. Sanjuan et al.

    Toll-like receptor signaling in the lysosomal pathways

    Immunol Rev

    (2009)
  • E. Jacquin et al.

    Imaging noncanonical autophagy and LC3-associated phagocytosis in cultured cells

    Methods Mol Biol

    (1880)
  • T. Shintani et al.

    Autophagy in health and disease: a double-edged sword

    Science

    (2004)
  • T. Hara et al.

    Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice

    Nature

    (2006)
  • M. Komatsu et al.

    Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice

    J Cell Biol

    (2005)
  • View full text