ABOVE: Flies typically become worse at climbing walls as they age, but with increased Trio levels, middle-aged flies (blue) became nearly as agile as young flies (green). Elderly flies (red) still struggled. Marine Van Campenhoudt, Brian McCabe
Old age is accompanied by more than just wrinkles. With age, it typically becomes harder for people to walk, stand up, and move as they used to. This decline in mobility is in part mediated by the motor neurons that carry instructions from the brain to the muscles. When a person wants to raise their arm, for example, chemical signals pass from the brain to motor neurons to an arm muscle to tell it to contract. As people age, their motor neurons become less adept at relaying these signals.
In a study published in Cell Reports, researchers identified a protein that seems to keep motor neurons spry.1 Using a fruit fly model, researchers showed that it plays an important role in maintaining motor neurons’ ability to send messages to muscles—and modulating its levels could help preserve mobility during aging.
“It gives us some hope that the downward [motor function] decline can actually be slowed,” said Brian McCabe, a neuroscientist at the Swiss Federal Institute of Technology Lausanne and coauthor of the study.
Neurons’ complex structures enable them to receive and transmit signals across synapses. McCabe’s team is interested in a specific part of this structure: the synaptic boutons, zones at the end of neurons where neurotransmitter molecules released by one cell trigger the next cell. In a previous study, they observed that the boutons responsible for relaying signals to muscles broke down into smaller regions that became less effective at releasing neurotransmitters in aging fruit flies.2
Although McCabe and his team could see the structural change, the researchers didn’t know what molecules triggered this transformation. This prompted them to investigate proteins that give neurons their shape, and they stumbled upon a familiar name: Trio. Nearly a decade earlier, they found that the protein enables proper synapse maturation.3 Now, with additional experiments, they showed that Trio is specifically located in the part of the synapse that releases neurotransmitters and that its levels decline as flies age.
To test whether Trio was to blame for the degradation of the boutons, the researchers modulated the protein’s levels in young flies. When they genetically decreased Trio levels, synaptic boutons broke up much more rapidly as the flies got older. When they overexpressed the protein, the synaptic structures were almost entirely preserved.
“It was very surprising how well Trio worked at rescuing the synapses,” McCabe said.
But it wasn’t enough that Trio kept the synapses looking youthful—for Trio to mediate motor function, it also needed to preserve mobility. To study this, the researchers set up an obstacle course of sorts that tested how well the flies climbed up the side of a tube, a task that flies begin to struggle with as they age. However, when the researchers increased Trio levels in the flies’ motor neurons, middle-aged flies became substantially better at scaling the tube. Their synapses released more neurotransmitters than flies with Trio levels typical for their age.
“It is very surprising to find [that] Trio has such specific effects on morphology, and that the morphological effects are enough to then feed back to function,” said Edward Giniger, a neuroscientist at the National Institute of Neurological Disorders and Stroke, who was not involved in this study. “It gives us a new way to think about the crosstalk between morphology and function.”
But Trio is not quite the fountain of youth. When the researchers investigated markers of aging in the flies’ cells, they saw that the cells still seemed to be aging as usual. “It was like plastic surgery,” McCabe said. “The synapses looked better on the outside, but they were still older on the inside.”
Additionally, high levels of Trio gave middle-aged flies a boost but as they got older, their climbing ability declined, nonetheless. McCabe suspects that even though Trio maintains motor neurons’ abilities to transmit signals, that is just one part of the motor decline that comes with aging.
Giniger, who has studied Trio’s role in neurodevelopment, said the new study gave him a lot to think about, especially with regards to Trio’s role in aging.4 “This is a beautiful example of why we still do studies in Drosophila,” he said, highlighting the way the experiments linked events at the molecular scale with both cellular and behavioral changes. He also said, however, that these findings in flies may not necessarily translate to humans. “These ideas need to go back and be retested in mammalian systems,” he said. McCabe is optimistic that, given Trio’s presence in mammalian synapses and role in diseases like autism, it may be important for human neuronal function as well.
McCabe’s team is currently searching for other proteins that interact with Trio to orchestrate motor function. In doing so, they hope to uncover the mechanisms that trigger bouton fragmentation and find new molecular solutions for slowing that process. Even if motor decline can’t be prevented entirely, the ability to delay it could be highly beneficial, McCabe said.
“This is the concept of health span, where you increase the time when you are in a healthier state,” he said. “If you are in a healthier state, you may be able to do more activities for longer.”
References
1. Banerjee S, et al. Trio preserves motor synapses and prolongs motor ability during aging. Cell Rep. 2024;43(6):114256.
2. Banerjee S, et al. Miniature neurotransmission is required to maintain drosophila synaptic structures during ageing. Nat Commun. 2021;12(1):4399.
3. Choi BJ, et al. Miniature neurotransmission regulates drosophila synaptic structural maturation. Neuron. 2014;82(3):618-634.
4. Song JK, Giniger E. Noncanonical notch function in motor axon guidance is mediated by Rac GTPase and the GEF1 domain of trio. Dev Dyn. 2011;240(2):324-332.