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

Autophagy. 2024 Feb 27. doi: 10.1080/15548627.2024.2322420. Online ahead of print.ABSTRACTA 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 correlated 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 in C. elegans aging, extending beyond their canonical degradative functions in the autophagy process.PMID:38411179 | DOI:10.1080/15548627.2024.2322420
Source: Autophagy - Category: Cytology Authors: Source Type: research