ATG14 and STX18: gatekeepers of lipid droplet degradation and the implications for disease modulation.

Lipophagy, a form of autophagy specific to the degradation of lipid droplets (LDs), plays an important role in the maintenance of cellular homeostasis and metabolic processes. A recent study has identified ATG14 (autophagy related 14) as a molecule that targets LDs and marks them for degradation via lipophagy; a process that is inhibited by the binding of STX18 (syntaxin 18) to ATG14 in mammalian cells. The exact mechanism of regulation of lipophagy, and subsequently of cellular LD levels, is still under investigation; however, dysregulation of this process has been linked to a number of disease phenotypes. An imbalance of lipid levels can result in a wide variety of conditions depending on the cell/tissue type in which they occur. In cells of the retinal pigment epithelium, lipid accumulation can result in dry age-related macular degeneration, in hepatocytes it can result in nonalcoholic fatty liver diseases and in neural cells it can result in the pathogenesis of neurodegenerative conditions such as Alzheimer and Parkinson diseases. Based upon its wide range of implications in diseases, modulation of lipophagy is currently being further investigated for its potential as a treatment for a variety of conditions ranging from viral infection to developmental illnesses.

Bruchpiloting synaptic connections: Egfr in autophagy-mediated neuronal circuit development.

Macroautophagy/autophagy is involved in many aspects of human development including the formation of neuronal circuits. A recent study from Dutta et al. found that the recruitment of Egfr (Epidermal growth factor receptor) to synapses suppresses autophagic degradation of presynaptic proteins, a requirement for proper neuronal circuit development. The findings suggest that Egfr inactivation during a distinct critical interval in late development results in increased levels of autophagy in the brain and decreased neuronal circuit development. Furthermore, the presence of brp (bruchpilot) in the synapse is critical for proper neuronal functioning over this same period. Dutta and colleagues found that increased autophagy due to Egfr inactivation results in decreased brp levels and, therefore, reduced neuronal connectivity. Through live cell imaging, it was determined that only the synaptic branches that accumulate both Egfr and brp are stabilized, allowing for the persistence of active zones, further supporting the importance of both Egfr and brp in the brain. While Dutta and colleagues collected these data based on studies conducted on Drosophila brains, the findings provide great insight as to how these different proteins may be implicated in human neurology.