Abstract
Autophagy is an evolutionarily conserved degradation process maintaining cell homeostasis. Induction of autophagy is triggered as a response to a broad range of cellular stress conditions, such as nutrient deprivation, protein aggregation, organelle damage and pathogen invasion. Macroautophagy involves the sequestration of cytoplasmic contents in a double-membrane organelle referred to as the autophagosome with subsequent degradation of its contents upon delivery to lysosomes. Autophagy plays critical roles in development, maintenance and survival of distinct cell populations including neurons. Consequently, age-dependent decline in autophagy predisposes animals for age-related diseases including neurodegeneration and compromises healthspan and longevity. In this review, we summarize recent advances in our understanding of the role of neuronal autophagy in ageing, focusing on studies in the nematode Caenorhabditis elegans.
Highlights
Autophagosome formation is driven by the orchestrated action of approximately 20 ATG proteins, whose role is essential for autophagic delivery of cargo to the lysosome or vacuole in yeast (Figure 1B,C) [9,10,11,12,13]
Focusing on research in the nematode C. elegans, we summarize recent advances in our understanding of the role of general and selective neuronal autophagy modulation in neuroprotection as well lifespan and healthspan regulation
Disrupted protein homeostasis causes nuclear translocation of HLH-30/TFEB, in order to induce expression of genes involved in lysosomal function and autophagy, as well as progranulin
Summary
Autophagy is an evolutionarily conserved process enabling cells to regulate a plethora of catabolic needs. Unfolding of the substrate and translocation via the receptor LAMP2A (lysosome-associated membrane protein type 2A) leads to the degradation of the substrate. Hallmark of autophagy is the de novo formation of a double-membrane vesicle, termed the autophagosome, which sequesters and engulfs cytoplasmic material (Figure 1A). Autophagosome formation is driven by the orchestrated action of approximately 20 ATG (autophagy-related) proteins, whose role is essential for autophagic delivery of cargo to the lysosome or vacuole in yeast (Figure 1B,C) [9,10,11,12,13]. ULK1 complex triggers the nucleation of an autophagosome membrane precursor, termed isolation membrane or phagophore by phosphorylating members of the PI3KC3 (class III phosphatidylinositol-3 kinase) complex I [VPS34 (vacuolar protein sorting 34), Beclin 1, ATG14, AMBRA1 (activating molecule in Beclin 1-regulated autophagy protein 1) and general vesicular transport factor (p115)]. Role for autophagy in animal health [27,28]
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