Clustering around condensates
A dynamic Woods Hole collaboration explores condensates in the nervous system, in health and in disease
image: Jennifer Morgan (Marine Biological Laboratory or MBL) and Dragomir Milovanovic (German Center for Neurodegenerative Diseases (DZNE) have formed a large collaboration at the MBL to understand how biomolecular condensates affect synaptic transmission, in health and in disease.
Credit: Marine Biological Laboratory
By Diana Kenney
“There was no way we could not collaborate,” says Dragomir Milovanovic of the German Center for Neurodegenerative Diseases, referring to Senior Scientist Jennifer Morgan of the Marine Biological Laboratory (MBL).
When the two first met in 2018, Milovanovic was exploring how condensates -- liquid-like droplets that spontaneously form inside cells -- behave in the nervous system, especially at the synapse, the important contact point where two nerve cells communicate. Morgan, meanwhile, was studying how the synapse malfunctions in devastating diseases such as Parkinson’s and Lewy body dementia.
Milovanovic’s studies were in vitro (in glass) – in artificial synapses built in a lab dish. Morgan’s were in vivo (in a living organism) – in the sea lamprey, which boasts giant synapses in some of its neurons.
“We clicked very well, very quickly,” says Milovanovic. “The secret of our success is our complementarity. We are interested in the same questions, but we take different approaches.”
“It’s like cosmic forces brought us together,” says Morgan, who first invited Milovanovic to the MBL in 2018 to give a seminar in the Eugene Bell Center, which she directs.
Of course, it helps that the MBL is Grand Central for the study of condensates. First observed during the 2008 MBL Physiology course, condensates are now known to form in all cells of the body and to regulate many critical cellular processes. They’ve also been implicated in the development of many serious diseases, including neurodegenerative disease.
Milovanovic’s in vitro approach “is very powerful to study how condensates form – the so-called liquid-liquid phase transitions,” he says. To translate this understanding to a living nervous system, “the sea lamprey synapse is absolutely second to none, in terms of its size and the imaging approaches you can use for visualizing its substructures,” he says.
The MBL “Metaverse”
The two scientists joined forces in January 2020 and have interacted ever since, with Milovanovic spending three full summers collaborating in residence in Morgan’s lab as a Whitman Fellow.
“Very importantly, our team members also collaborate,” Milovanovic says. “All my lab members have now visited MBL as part of the Whitman program. So, beyond our shared scientific interests is community building, which is very important to me. We have a sort of big lab, like a merger of two labs.”
Good news travels fast, and the Morgan-Milovanovic collaboration has now reached into nearly all corners of the MBL campus, including what he calls the Whitman “metaverse.”
“A really important cluster of people in the Whitman Center is studying condensates,” he says. They also interact with the MBL Physiology course co-directors, both world leaders in condensate biology: Cliff Brangwynne of Princeton University, who co-founded the field after observing condensates form in cells during the 2008 MBL Physiology course, and Amy Gladfelter of Duke University. Resident MBL scientists also contribute to their extensive collaboration.
“It’s a very dynamic and diverse ecosystem of people,” Milovanovic says.
How Does All This Hold Together?
As Brangwynne and others first observed at MBL, cells spontaneously form condensates, or liquid-like droplets that concentrate some of the cell’s molecules in a membrane-free compartment. Condensates form by a phase separation process, similar to oil separating from water.
The Morgan-Milovanovic collaboration focuses on how condensates organize synaptic function, both in health and in disease. One key process is the cycle in which synaptic vesicles -- small, membrane-bound sacs that store neurotransmitters, the chemical messengers of nerve cell communication -- release their contents and then are recycled again, for neurotransmission to continue.
The synapse contains thousands of synaptic vesicles that are “stuck together like a package, but with no delimiting membrane, no scaffolding holding it all together. And it has been a puzzling question, what keeps the vesicles clustered together in such a dynamic form? Why don’t they just disperse away and equalize?” Milovanovic says. “And here, the principles of phase separation are helping us understand why.”
These big clusters of synaptic vesicles – which we now know represent condensates -- are found dotted along the surface of the axon, the long, thin extension of the nerve cell. So how are these condensates, which have no membrane, interacting with the membrane of the axon? That’s a key question that the two are pursuing. And it relates to Morgan’s work in synaptic dysfunction in neurodegenerative disease.
Toward a Treatment for Parkinson’s Disease
Morgan studies a protein called alpha-synuclein, which builds up abnormally in the brains of patients with Parkinson’s disease.
“If you have too much alpha-synuclein at the synapse, it gets extra sticky and the synaptic vesicles can’t move around properly,” Morgan says.
“So, one idea for developing a strategy to treat Parkinson’s disease is to titrate the synuclein off the axonal membrane,” she says. “You don’t want to remove it, because you need it for normal function. But if there is too much and it’s sticking onto the membranes and not allowing proper phase separation of the vesicle clusters, you might want to tweak it by titrating a little bit off, using rationally designed synuclein inhibitors.”
Morgan is collaborating with a few labs and companies to explore this idea, based on the principles of membrane binding.
“We are using different models to test whether these inhibitor drugs could improve the situation, whether it’s looking at neuronal death in a mammalian Parkinson’s disease model or looking at synaptic vesicle correction at the lamprey synapse,” Morgan says. “That kind of preclinical work with synuclein inhibitors is being done around the world right now.”
“This collaboration represents MBL at its best,” says MBL Director of Research Anne Sylvester. “The MBL provided the environment for an important basic discovery to be made and then to grow, by attracting scientists from all over the world to collaborate in its intensive, exciting research environment.”
“We are thrilled to see this work heading toward making an impact in treating neurodegenerative diseases that afflict millions of people around the world,” Sylvester says.
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Listed below are publications from the Milovanovic-Morgan collaboration, with more in the pipeline!
Chhabra A, Hoffmann C, Aguilar Perez G, Korobeinikov A, Rentsch J, Huempfer N, Kokwaro L, Gnidovec L, Petrovic A, Wallace J, Tromm JV, Cristina RV, Johnson E, Rankovic B, Perego E, Volpi T, Fernandez-Busnadiego R, Koester S, Rizzoli S, Ewers H, Morgan J, Milovanovic D. bioRxiv [Preprint]. 2025 Mar 29:2024.07.19.604346. doi: 10.1101/2024.07.19.604346.
Synapsin Condensation is Governed by Sequence-Encoded Molecular Grammars.
Hoffmann C, Ruff KM, Edu IA, Shinn MK, Tromm JV, King MR, Pant A, Ausserwöger H, Morgan JR, Knowles TPJ, Pappu RV, Milovanovic D. J Mol Biol. 2025 Apr 15;437(8):168987. doi: 10.1016/j.jmb.2025.168987.
Wallace JN, Crockford ZC, Román-Vendrell C, Brady EB, Hoffmann C, Vargas KJ, Potcoava M, Wegman ME, Alford ST, Milovanovic D, Morgan JR. Mol Biol Cell. 2024 Jan 1;35(1):ar10. doi: 10.1091/mbc.E23-07-0269.
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