Enhancing neuronal reticulophagy: a strategy for combating aging and APP toxicity.

Reticulophagy, which directs the endoplasmic reticulum (ER) to the phagophore for sequestration within an autophagosome and subsequent lysosomal degradation via specific receptors, is essential for ER quality control and is implicated in various diseases. This study utilizes to establish an model for reticulophagy. Starvation-induced reticulophagy is detected across multiple tissues in . Whole-body upregulation or downregulation of the expression of reticulophagy receptors, and , negatively affects fly health. Notably, moderate upregulation of reticulophagy in neuronal tissues by overexpressing these receptors reduces age-related degeneration. In a Alzheimer model expressing human APP (amyloid beta precursor protein), reticulophagy is compromised. Correcting reticulophagy by enhancing and expression in the neurons promotes APP degradation, significantly reducing neurodegenerative symptoms. However, overexpression of mutated and , which disrupts the interaction of the corresponding proteins with Atg8, does not alleviate these symptoms, emphasizing the importance of receptor functionality. These findings support modulating reticulophagy as a therapeutic strategy for aging and neurodegenerative diseases associated with ER protein accumulation.