July 11, 2022

By Christopher Vaughan

A tiny marine creature with a strange lifestyle may end up giving us valuable insights into human neurodegenerative disorders like Alzheimer’s disease, say scientists at Stanford School of Medicine. 

Botryllus schlosseri, also called the star tunicate, is most visible as a tiny flower-shaped organism that attaches to rocks along the coast. It is also humans’ closest evolutionary relative among invertebrates in the seas. It starts life swimming in the ocean as a tiny tadpole-like creature with two brains, but then at some point it drifts down from the surface to settle into a stationary life on a rock, joining a colony of invertebrate organisms. 

As it adapts to a sedentary life on the rock, like a human couch-potato, the tunicate loses brain power—one of the two brains, now unneeded for navigating the seas, is dissolved. But the way the brain degenerates and disappears has important parallels to the way the brain degenerates in human neural disorders, says Irv Weissman, MD, director of the Institute for Stem Cell Biology and Regenerative Medicine. 

In a paper published this week in the Proceedings of the National Academy of Sciences (PNAS), Weisman and his colleagues show that many of the genes associated with neurodegeneration in Botryllus have analogues to the genes associated with neurodegeneration in humans. What’s more, the researchers say, genetic changes that build up over decades in the Botryllus colonies  affect neurodegeneration in many of the same ways as age-relationed genetic changes affect elderly humans. 

“We think that Botryllus is the beginning of the vertebrate line,” Weissman said. “And although the path that led to humans split far back in time, the essential stuff might stay the same.” Weissman, who is the Louise and D.K. Ludwig Professor in Pathology, is the co-senior author on the PNAS paper, along with Stanford Senior Scientist Ayelet Voskoboynik, PhD who is leading studies on this marine organism at Stanford’s Hopkins Marine Station in Pacific Grove. Postdoctoral scholar Chiara Anselmi, PhD, is first author on the paper.

Botryllus offers a lot of advantages as a model organism for studying neurodegeneration, the researchers say. Every week, each Botryllus organisms in a colony reproduces a-sexually, producing 2-4 buds that become new organisms. Each bud complete its development within two weeks, lives as an adult for one week, and then deteriorates and dies on the the last day of the third week. 

“At the beginning we thought the number of neurons would be stable” during the adult stage during the third week, Anselmi said. “But the number is not stable, there is a specific pattern of neural degeneration.” What’s more, the process of neural degeneration is very similar to that in humans. “Out of about 1,000 genes that are involved in neural degeneration, we found that 428 are homologous genes shared by humans and Botryllus.” So being able to study the process of neural degeneration in Botryllus may tell us a lot about neural degeneration in humans.

Things really get interesting when they looked at neural degeneration in the aged Botryllus colonies. One challenge when using mice to study humans neural degeneration is that the degenerative process is thought to be driven in part by changes that accumulate in neural stem cells over decades. But mice reach old age and die in about 3 years, long before they acquire the kinds of stem cell alterations that human have in old age. The Botryllus colonies at the Stanford Hopkins Marine Station in Pacific Grove have been around for over 20 years, however. Since the organisms in the colony reproduce asexually through stem cell mediated organogenesis, their stem cells are the only cells in the colonies that maintained throughout the years and most likely  accumulate defects over time in the same way that ours will.

Elderly humans get neurodegenerative diseases more often than young people, and human neural stem cells are less active than they are when young. A similar pattern is seen in aged Botryllus colonies, which  regenerate smaller brains than young colonies. “Something happens to the stem cells in the colony along the way, and after 20 years, they can’t regenerate the way they did when they were young,” Voskoboynik said. “There is a reduction in neurons of almost 30 percent in individuals brains in the aged colony, and even at the peak of neural generation it doesn’t reach the peak of young colonies.” Future studies on the differences between young and old neural stem cells aged in this relatively simple model organism will shed light on their role in neurodegenerative diseases in elderly humans.    

“It is amazing that in an invertebrate you can see the same changes in genes from young to old that you see in aging humans,” Voskoboynik said.

Furthermore, the individuals in those aging colonies show definite parallels to people with Alzheimer’s disease, the neurodegenerative disease that usually strikes only in the last decades of life. One of the hallmarks of Alzheimer’s disease is the accumulation amyloid plaques, which are created when amyloid precursor proteins (APP) glom together. “When individuals in the aged colonies go through that asexual cycle, not only do they make far fewer neurons, but those neurons have a lot of APP,” Weissman said. 

Since no one yet knows the cause of Alzheimer’s disease or the significance of amyloid in the neurons, the researchers are hopeful that Botryllus might be a powerful platform for studying the disease. “We can easily create 250 offspring every week and study various aspects of their neural development and degeneration,” Weissman says. “We can put anti-sense signals in the water and block specific pathways that might lead to amyloid accumulation or other aspects of Alzheimer’s neurodegeneration.”

“Even though we are way behind the fly and mouse people in terms of understanding neural stem cells and the formation of brains in Botryllus, we believe this is an ideal animal to look through the window of so many biological processes that they share with humans,” Weissman said.

This study was supported the National Institutes of Health (R01AG037968, RO1GM100315, R21AG062948), the Chan Zuckerberg Biohub, the Stinehart-Reed Foundation, Progetti di Ricerca di Ateneo (CPDA153837), the Larry L Hillblom Foundation, the Aldo Gini Foundation and the University of Padova.