Chapter Thirteen - Genetic defects of autophagy linked to disease
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
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