Most drugs cannot get across the blood-brain barrier into the brain, impeding the treatment of cancer and many neurological disorders. Even essential brain nutrients must be transferred through special transporter proteins embedded in the barrier's membrane.
New findings from researchers at Columbia University Vagelos College of Physicians and Surgeons and UCSF now suggest that one of these transporters, a protein that carries the nutrient choline, could potentially be exploited to carry therapeutic drugs into the brain.
Choline transporter. A new study has found that the FLVCR2 protein (colored portions in images above) is responsible for transporting choline, an important nutrient for brain development and function, across the blood-brain barrier. The structure of the choline transporter (shown in two different conformations) suggests it may transport other molecules and could be utilized to transport new neurotherapeutics. Images from Cater, et al.
The transporter, called FLVCR2, had no known function until the researchers began investigating it.
In the new study, the team discovered that FLVCR2 is the primary transporter of choline into the brain. The brain requires a large and regular supply of choline for its neurons to function properly, but how this essential nutrient crosses the blood-brain barrier had long eluded researchers.
Work by Rosemary Cater, a postdoctoral researcher in the Columbia laboratory of Filippo Mancia, professor of physiology & cellular biophysics, then showed how FLVCR2 carries choline into the brain.
"We used high-powered cryo-electron microscopes to see exactly how choline binds to FLVCR2 at different stages of its transport cycle," she says.
These images revealed that choline is kept within a cage of protein residues as it travels through the interior of the FLVCR2 transporter.
"This is critical information for understanding how to design drugs that mimic choline so that they can be transported by FLVCR2 to reach their site of action within the brain," says Cater, who is now a group leader and senior research fellow at the University of Queensland.
| Breaking through the blood-brain barrier. The blood-brain barrier protects the brain from toxins, but prevents most potential neurotherapeutic drugs from reaching the brain. During her postdoc in Filippo Mancia's laboratory at Columbia University Vagelos College of Physicians and Surgeons, Rosemary Cater focused on how molecular transporters shuttle nutrients across the blood-brain barrier to learn how drugs could be designed so they are carried by the same transporters. In addition to solving the structure of the choline transporter, she determined the structure of the omega-3 fatty acid transporter (published in Nature in 2021). Cater was a junior fellow of the Simons Society during her postdoc and a regional finalist in 2022 for the Blavatnik Award for Young Scientists. In 2024 Cater was appointed as senior research fellow and group leader at the University of Queensland's Institute for Molecular Bioscience. |
Experiments performed predominantly in the laboratory of Matthias Quick, associate professor of neurobiology (in psychiatry) at Columbia, also raised the possibility that the transporter moves additional molecules through the blood-brain barrier. "If so, we might be able to take advantage of this mechanism to deliver novel neurotherapeutics into the brain," Mancia says.
The team's UCSF researchers, led by Thomas Arnold, MD, had previously discovered that mutations in the FLVCR2 gene cause brain development disorders, including a rare disease called Fowlers syndrome, a rare form of congenital hydrocephalus, a disease with few if any good treatments.
The new findings could explain how mutations in FLVCR2 disrupt choline transport and lead to symptoms seen this syndrome, raising the possibility of fixing the defect to treat this and related diseases.
"I'm especially excited about the potential implications to human health, which range from understanding how our diet affects important pediatric neuro-developmental diseases to identifying new ways to get drugs into the brain," Arnold says.
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The study is titled, "Structural and molecular basis of choline uptake into the brain by FLVCR2."
Mattias Quick is also professor of physiology & cellular biophysics at Columbia University Vagelos College of Physicians and Surgeons.
The other contributors are: Dibyanti Mukherjee (UCSF), Eva Gil-Iturbe (Columbia), Satchal K. Erramilli (University of Chicago), Ting Chen (Columbia), Katie Koo (UCSF), Nicolás Santander (Universidad de O'Higgins, Chile), Andrew Reckers (Columbia), Brian Kloss (Columbia), Tomasz Gawda (University of Chicago), Brendon C. Choy (Columbia), Zhening Zheng (Columbia), Aditya Katewa (UCSF), Amara Larpthaveesarp (UCSF), Eric J. Huang (UCSF), Scott W. J. Mooney (Burke Neurological Institute), Oliver B. Clarke (Columbia), Sook Wah Yee (UCSF), Kathleen M. Giacomini (UCSF), Anthony A. Kossiakoff (University of Chicago), and Matthias Quick (Columbia and New York State Psychiatric Institute).
This work was supported by a grant from the National Institutes of Health (R21NS129105-01).
The authors declare no competing interests.
