The human brain is capable of cleaning up debris left over from cellular activity on its own. While this fact has been known for years, scientists have struggled to understand exactly how the brain knows to initiate these cleaning mechanisms. Finally, a team of researchers led by scientists at Yale School of Medicine may have found an answer.
In their study, researchers identified the ATG-9 protein. This protein plays an integral role in cleaning the brain of debris, a process also known as autophagy. ATG-9 is responsible for measuring synaptic activity and alerting when there is a need for increased autophagy, a function in which neuronal debris generated by an uptick in activity is surrounded and broken down.
A possible explanation for autophagy’s lack of performance under increases in synaptic activity may be found in the mutations that influence ATG-9 trafficking at neuronal synapses. This deficit, researchers noted, has been connected to multiple neurodegenerative diseases such as Parkinson’s disease.
“Neurons are frequently active and their machineries are subject to wear and tear,” says Daniel Colón-Ramos, the paper’s senior author and a professor of neuroscience and cell biology, in a statement.
How ATG-9 proteins stimulate ‘cleaning’ of the brain
Cell “cleanup,” or cellular degradation, grows more necessary as neuronal activity increases. Autophagy clears the brain of the waste created by increased activity through neurons which create an organelle capable of isolating, carrying, and degrading damaged cellular components. Scientists have sought to understand how these organelles are formed, as it is not yet clear how neurons work to initiate the process.
Using genetic molecular approaches, researchers monitored the activity of ATG-9 proteins to understand mechanisms key to autophagy. In their study, they found that ATG-9 monitors neuronal activity through a process known as the synaptic vesicle cycle. During this cycle, neurotransmitters responsible for facilitating brain functions are secreted from cells. As activity increases in the synapses, the synaptic vesicle cycle and ATG-9 trafficking increases along with it, alerting a need for a cellular cleaning via autophagy.
“We think that as these neurons perform their function and transmit information, ATG-9 acts as a sort of activity log which, when neuron activity increases, helps alerts cells to produce more autophagy for future cleanups,” Sisi Yang, first author for the paper and a doctoral candidate at Yale. “Therefore, ATG-9 acts like a coordinator of synaptic activity and autophagy.”
Findings could lead to new treatments?
Additional applications of their findings may provide a needed understanding of neurodegenerative disease processes linked with an impairment to the autophagy function. Researchers have also identified multiple mutations causing detrimental effects to the synaptic trafficking of ATG-9, which limits the capacity of neurons to boost autophagy after an increase in neuronal activity. One such mutation, they found, is a human genetic mutation linked to Parkinson’s disease.
“We find that in both vertebrate and invertebrate neurons, affecting ATG-9 trafficking at the synapse affects the ability of neurons to induce activity-dependent autophagy,” Colón-Ramos said. “The fact that these same genetic lesions have been associated with neurodegenerative disorders now provide targets to reactivate these housekeeping processes, perhaps preventing the neuronal dysfunction observed in neurodegenerative diseases.”
This study is published in Neuron.
Article written by Anna Landry
