Monica Driscoll, professor in the department of molecular biology and biochemistry at Rutgers University, will give an Apex Lecture on Monday, Jan. 8 at 4:00 p.m. CT in 1220 MRBIII.
Her talk, “Neurons Put Out the Trash: Modeling Aggregate and Organelle Transfer in a Living Nervous System” is hosted by the School of Medicine Basic Sciences and co-sponsored by the Vanderbilt Center for Extracellular Vesicle Research.
“Most interesting to our research community in the Vanderbilt Center for Extracellular Vesicle Research has been Driscoll’s discovery of gigantic neuronal extracellular vesicles called exophers,” said Alissa Weaver, professor of cell and developmental biology and director of the Vanderbilt Center for Extracellular Vesicle Research. “Her team painstakingly documented the previously unknown release of exophers from neurons in C. elegans worms and have gone on to define a key role for exophers in disposing of toxic protein aggregates from cells. This work has enormous implications for neurodegenerative disease, and I’m excited to see where it leads.”
With a career start on necrotic cell death mechanisms and their molecular underpinnings, Driscoll progressed into the study of the fundamental processes that can improve and maintain neuronal functionality with age. Her lab is conducting data-driven testing of potential pharmacological anti-aging interventions in diverse nematode populations, deciphering of the molecular mechanisms by which exercise promotes neuronal and organism health, and defining the basic biology by which neurons manage aggregate and organelle waste to maintain functionality. Another interest in the Driscoll lab is in how the stress of space travel conditions influence health and aging in Caenorhabditis elegans, with a current project focused on the impact of the microbiome on physiology under microgravity conditions at the International Space Station.
“Monica has followed a simple yet extremely effective strategy over her career,” Weaver said. “She asked the simple question that many others overlooked: what does aging look like? Her observations that worms age much like we do, from the degenerative effects of a stroke-like event to the slow loss of muscle tone and physical ability, led her to identify conserved mechanisms underlying age-related deficiencies in worms and humans. Notably, her willingness to keep pulling the thread when she uncovers a weird result has led to some of her most fascinating revelations.”
Driscoll, who was enrolled in the Douglass Residential College during her undergraduate studies at Rutgers University, earned a bachelor’s degree in chemistry, followed by a Ph.D. in biochemistry and molecular biology at Harvard University, studying molecular and genetic regulation of gene expression in a yeast model system.
She pursued postdoctoral studies at Columbia University, where she began her work on the simple animal C. elegans, focusing on deciphering molecular mechanisms of mechanotransduction and necrotic neuronal degeneration, and then joined Rutgers University as a faculty member in 1991. She is a fellow of the American Association for the Advancement of Science and a member of the Genetics Society of America and the Gerontological Society of America. Recognitions she has received include an NIH Merit Award, an appointment to the National Advisory Council on Aging (service completed in 2023), a Glenn Foundation Award for Research on Biological Mechanisms of Aging, an Ellison Medical Foundation Senior Scholar Award, and an appointment as Alfred P. Sloan Research Fellow.
About the Apex Lecture Series
To highlight major inflection points in research, the Vanderbilt School of Medicine Basic Sciences launched the Apex Lecture Series in 2023 to encourage the Vanderbilt and Vanderbilt University Medical Center basic sciences community to engage with researchers from around the world who are influencing the trajectory of their fields.
Lecture abstract
Proteostasis disruption is a major contributor to neurodegenerative disease and to age-associated decline in cognition. In recent years, the importance of small and large extracellular vesicles in animal health and function have become increasingly apparent. We discovered that C. elegans adult neurons can extrude large vesicles (~5 µM, 100X larger than exosomes) that we call exophers. Exophers can carry potentially deleterious proteins and organelles out of the neuron and can hand these materials off to neighboring glial-like cells. Inhibiting chaperone expression, autophagy, or the proteasome, as well as over-expressing aggregating proteins like human AD Aβ1-42, expanded polyglutamine Q128 protein, or high concentration mCherry increases exopher production from the affected neurons. Neurons that express proteotoxic transgenes maintain higher functionality if those neurons produce exophers as compared to those that do not, suggesting that exopher-genesis can be neuroprotective. Recent studies in mammalian models report exopher-like biology in higher organisms, including in human brain. Overall, data are converging to support that the mechanism by which an exopher is produced is a likely conserved process that constitutes a fundamental, but formerly unrecognized, branch of neuronal proteostasis and stress response.
We have taken genetic and cell biological approaches to dissecting the mechanisms by which neurons distinguish the garbage they will throw out, how they store threatening material and transport it for extrusion, how the health of the sending neuron is altered by the exopher event, how the extruded exopher is recognized for degradation by a surrounding cell, and how exopher-genesis is triggered and regulated. I will touch on these approaches in describing our current understanding of exopher biology as a facet of proteostasis.