Meet Sisi Yang, a PhD candidate in the Colón-Ramos Lab! Her exciting new paper published in Neuron uncovers a missing link between autophagy and synaptic activity.
In Greek, autophagy means “self-eating.” In neurons, autophagy means it’s time to clean up trash. This cellular degradative pathway is especially important when the brain is hyperactive — however, it is unknown how autophagy knows when to turn on and signal this need for neurons. This became a fascinating question for Yang during her graduate school journey.
"Although recent evidence shows that increased autophagy responds to increased neuronal activity, it is mysterious how autophagy connects and dials with the activity state of the neurons,” Yang said. “I am so excited to discover that an essential autophagy protein ATG-9 can undergo a machinery called "exo-endocytosis", which is similar to a cycle at synapses coupled with synaptic activity. "
Exo-endocytosis is ultimately important for degradation in neurons. Yang found that disruption of this ‘cycle’ not only affects ATG-9 localization, but also the autophagy at synapses. It excited Yang to dig into a question throughout her graduate studies, and in the end, reveal an answer for which scientists had been searching for years.
Three moments proved crucial to this discovery during her research. The first was when she found out that the “mysterious ATG-9 structures” were important intermediates that formed during the synaptic vesicle cycle — a cycle that controls neuronal activity. The second moment was when Yang found out that mutations that disrupted the ATG-9 "cycle" also caused a defect in the autophagy pathway.
“This made me realize that the ‘cycle’ of ATG-9 is important for degradation in neurons. The third moment is that I tried many methods and found out that the ATG-9 ‘cycle’ could be predictably manipulated when I changed the neuronal activity.”
As an undergraduate at Peking University, Yang had not only conducted research locally, but also went abroad for a research internship in Derek Toomre’s lab — right here at Yale.
“I found it fascinating to make hypotheses and test them by experimental science during these experiences,” Yang said. “I also like Yale's research community, which is very open and has many exciting, new findings occurring everyday.”
Returning to Yale for her PhD, Yang ultimately chose the Colón-Ramos Lab. This decision enabled her to do genetic screens in the brains of C. elegans, leading to “unexpected” results and subsequent discovery.
Yang plans to continue investigating molecular mechanisms that are important for neurons to maintain their functions during stress, aging, or high metabolic activity states. In the long run, she hopes to become an independent researcher who leads a team to study these questions.