Neuronal waste management: new roles for autophagy genes in the extrusion of protein aggregates and in longevity

Abstract

A decline in macroautophagic/autophagic activity with age contributes to the accumulation of damaged molecules and is associated with the impairment of neuronal functions and the onset of age-related diseases, particularly neurodegenerative disorders. To learn about the neuronal-specific roles of autophagy genes in aging, we specifically inhibited autophagy genes pan-neuronally in C. elegans, which leads to unexpected positive impacts on neuronal homeostasis including polyQ aggregate load and organismal lifespan. These improvements are independent of canonical, degradative autophagy in neurons and instead correlate with an increase in the secretion of large, extracellular vesicles, known as exophers. We found that the ATG-16.2 WD40 domain, a conserved domain critical for at least some noncanonical autophagy functions of ATG16L1 in mammalian cells, is required for the increased exopher biogenesis, reduction in polyQ aggregate load, and lifespan extension induced by neuronal inhibition of early-acting autophagy genes. Our study suggests that noncanonical functions of ATG-16.2, and potentially other early-acting autophagy genes, may play a role in neuronal exopher formation and C. elegans aging, extending beyond their canonical degradative functions in the autophagy process.

Keywords: ATG-16.2/ATG16L1; Aging; C. elegans; exophers; non-canonical autophagy.

Figure 1.

The WD40 domain of ATG-16.2 plays a critical role in facilitating exopher formation, improving neuronal proteostasis, and promoting longevity in C. elegans. Knockdown of early-acting autophagy genes—those involved in the formation of autophagosomes—has a positive impact on lifespan, neuronal proteostasis, and neuronal functions in C. elegans. These effects are dependent on the WD40 domain of neuronal ATG-16.2, which is also required for the formation of exophers, large vesicles that are extruded from the soma of neurons. Exophers can contain potentially neurotoxic proteins, and the amount of exophers formed in touch neurons correlates with the benefits upon knockdown of early-acting autophagy genes. Given the reported non-canonical functions of the ATG16L1 WD40 domain in mammalian cells, this highlights the possibility that non-canonical functions of specific autophagy genes are critical for both exopher formation and aging, potentially in a conserved fashion. See the text for details.