Understanding the mechanisms of neuronal secretory autophagy

ongoing

Neurons transmit information by connecting with other neurons over long distances through their dendrites and axons. Repeated stimulation places a high metabolic demand on these cells, leading to the accumulation of defective organelles and protein aggregates. To maintain protein homeostasis, neurons rely on constitutive autophagy to remove these damaged proteins and organelles from their dendrites and axons, targeting them for degradation. However, it is becoming increasingly clear that neurons also secrete a part of this autophagic cargo into the extracellular space. The mechanisms governing neuronal secretory autophagy are still poorly understood. The factors that determine whether autophagic cargo is degraded or secreted, as well as the precise neuronal location from which secretory autophagy occurs, remain unknown. Understanding these mechanisms is highly relevant in neurodegenerative diseases, such as Alzheimer’s disease, where the balance between degradative and secretory autophagy is disrupted. In this interdisciplinary project, I will use human iPSC-derived neurons and develop novel molecular tools to elucidate the mechanisms underlying neuronal secretory autophagy. I will employ state-of-the-art bioluminescent and fluorescent reporters to characterize this process with high spatiotemporal resolution, leveraging my experience in studying exosome release during my PhD. Furthermore, I will apply the host lab’s expertise in proximity labeling and chemogenetic relocalization to identify key regulators of neuronal secretory autophagy and explore the potential of modulating secretory autophagy in a cell model for Alzheimer’s disease. Ultimately, this project aims to provide fundamental insights into the mechanisms driving neuronal secretory autophagy and the potential for modulating this process in neurodegenerative diseases.