The Brain Takes Out the Trash

Image Courtesy of Coleen Murphy.

Cleaning our homes is an important chore, as the buildup of trash interferes with our productivity and invites disease. It is just as important for cells to break down and dispose of old or damaged components through a process known as autophagy. Autophagy is especially vital in neurons—our brain cells—because they must last an entire lifetime. Furthermore, autophagy issues are associated with neurodegenerative diseases due to the buildup of dysfunctional proteins. Despite their importance, the mechanisms of local autophagy in neurons are not completely understood. 

At the Colón-Ramos Lab at Yale, graduate student Sisi Yang used the microscopic roundworm C. elegans to study the fascinating cellular journey of ATG-9, a crucial protein for autophagy. Yang found that ATG-9 travels to the synapse, the junction at which two neurons communicate, in vesicles from the trans-Golgi network or membranous packages from the cell’s ‘shipping center.’ Then, at synapses, vesicles containing ATG-9 undergo exo-endocytosis, the process by which cells release signals to communicate with each other.

Abnormal accumulation of ATG-9 in neurons was observed in both mutant C. elegans with disrupted autophagy and mutants with disrupted endocytosis. By manipulating synaptic activity, Yang could control the ATG-9 trafficking into these abnormal accumulated structures, demonstrating links to defects in autophagy. Therefore, these findings led to the hypothesis that ATG-9 serves as a link between autophagy and neuronal activity. 

Interestingly, C. elegans with mutations found in Parkinson’s disease patients similarly exhibit abnormal ATG-9 accumulation and behavioral defects. According to Yang, the study’s findings could offer insights into how early-onset Parkinsonism could be linked to ATG-9 mislocalization or dysfunctional autophagy. Information about the involvement of ATG-9 in both autophagy and exo-endocytosis may help explain molecular mechanisms behind the disease, providing targets for future treatments.

Acknowledgment: The work was performed in collaboration with the laboratory of Yale University’s Pietro de Camilli and with the laboratory of Jihong Bai from the Fred Hutchinson Cancer Center.