Structure and mechanism of blood–brain-barrier lipid transporter MFSD2A

Wood, Chase; Zhang, Jinru; Aydin, Deniz; Xu, Yan; Andreone, Benjamin J.; Langen, Urs H.; Dror, Ron O.; Gu, Chenghua; Feng, Liang

doi:10.1038/s41586-021-03782-y

Cited by 59 publications

(87 citation statements)

References 58 publications

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“…Subsequently, we discovered that Wnt signaling mediates MFSD2A-dependent vascular EC transcytosis through a Cav1-positive caveolae pathway independent of clathrin-mediated transport. Furthermore, the levels of omega-3 polyunsaturated fatty acids are decreased in Wnt signaling-deficient retinas, consistent with the fundamental function of MFSD2A as a lipid transporter [ 79 ]. Consequently, MFSD2A/Cav1 signaling axis is a novel downstream effector of the Wnt/β-catenin signaling pathway in regulating EC transcytosis and iBRB integrity under physiological conditions and in development [ 17 ] ( Figure 5 ).…”

Section: Wnt Signaling and Ibrb Maintenancementioning

confidence: 61%

“…MFSD2A, selectively expressed in both brain and retinal microvessels, is a protein with dual roles in both lipid transport and transcytosis. MFSD2A assists brain uptake of docosahexaenoic acid (DHA) (an omega-3 polyunsaturated fatty acid, which is important for brain growth and function) in a form bound with lysophosphatidylcholine (LPC) [ 78 , 79 ]. In the eye, MFSD2A is also linked with an uptake of DHA in photoreceptors through transportation by the RPE in mice [ 80 ].…”

Section: Molecular Components Of the Ibrbmentioning

confidence: 99%

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Wnt Signaling in Inner Blood–Retinal Barrier Maintenance

Yemanyi

Bora

Blomfield

et al. 2021

IJMS

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The retina is a light-sensing ocular tissue that sends information to the brain to enable vision. The blood–retinal barrier (BRB) contributes to maintaining homeostasis in the retinal microenvironment by selectively regulating flux of molecules between systemic circulation and the retina. Maintaining such physiological balance is fundamental to visual function by facilitating the delivery of nutrients and oxygen and for protection from blood-borne toxins. The inner BRB (iBRB), composed mostly of inner retinal vasculature, controls substance exchange mainly via transportation processes between (paracellular) and through (transcellular) the retinal microvascular endothelium. Disruption of iBRB, characterized by retinal edema, is observed in many eye diseases and disturbs the physiological quiescence in the retina’s extracellular space, resulting in vision loss. Consequently, understanding the mechanisms of iBRB formation, maintenance, and breakdown is pivotal to discovering potential targets to restore function to compromised physiological barriers. These unraveled targets can also inform potential drug delivery strategies across the BRB and the blood–brain barrier into retinas and brain tissues, respectively. This review summarizes mechanistic insights into the development and maintenance of iBRB in health and disease, with a specific focus on the Wnt signaling pathway and its regulatory role in both paracellular and transcellular transport across the retinal vascular endothelium.

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Section: Wnt Signaling and Ibrb Maintenancementioning

confidence: 61%

Section: Molecular Components Of the Ibrbmentioning

confidence: 99%

Wnt Signaling in Inner Blood–Retinal Barrier Maintenance

Yemanyi

Bora

Blomfield

et al. 2021

IJMS

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“…As a newly identified essential inhibitor of BBB transcytosis, major facilitator superfamily domain-containing protein 2a (Mfsd2a) functions as a lipid transporter for the omega-3 fatty acid docosahexaenoic acid ( Fig. 2 ) [ 41 , 44 , 45 ]. Loss of Mfsd2a in mice led to increased permeability of BBB due to upregulated transcytosis [45] .…”

Section: Transport Across Blood-brain Barrier and Drug Delivery Strat...mentioning

confidence: 99%

“…Loss of Mfsd2a in mice led to increased permeability of BBB due to upregulated transcytosis [45] . The most recent structural definition of Mfsd2a increases the potential to modulate the BBB permeability by targeting Mfsd2a for efficient drug delivery [44] .…”

Section: Transport Across Blood-brain Barrier and Drug Delivery Strat...mentioning

confidence: 99%

The blood-brain barrier in health, neurological diseases, and COVID-19

Chen¹,

Tan

et al. 2022

Fundamental Research

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“… 12 More discoveries on the transit between cell types/subtypes, between acute and chronic conditions, between chronic disease and cancer, and between tumorigenesis and chromatin/epigenetic instability can be carried out by integrating molecular networks from multiomics and transomics with functions and regulations. Studies on the cryoelectron microscopy structure that functions similar to the major facilitator superfamily domain‐containing protein 2a (MFSD2A) demonstrated that this sodium‐dependent lysophosphatidylcholine symporter has a conserved sodium‐binding site as a potential lipid entry pathway, 13 which might be a druggable target for new drug identification and development.…”

mentioning

confidence: 99%

Discovery in clinical and translational medicine

Wang

Wang²

2021

Clinical & Translational Med

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With the rapid development of biotechnologies and deep improvement of knowledge, “Discovery” is the initial period and source of innovation of clinical and translational medicine. The international journal of Clinical and Translational Discovery serves to highlight unknown or unclear aspects of clinical and translational medicine‐associated knowledge, technologies, mechanisms, and therapies (https://onlinelibrary.wiley.com/journal/27680622). The Discovery aims to define the interaction between genes, proteins, and cells, and explore molecular mechanisms of intercommunication and inter‐regulation. More discoveries of technologies and equipment are expected to improve method sensitivity, specificity, stability, analysis, and clinical significance. The first priority of Clinical and Translational Discovery is to turn gene‐, protein‐, drug‐, cell‐, and interaction‐based discoveries into health advancements. Clinical and Translational Discovery highly focuses on the discoveries of biological therapies and precision medicine‐based therapy elicited from computational chemistry, DNA libraries, target‐dependent small molecular drugs, high‐throughput screening, vaccination, immune therapy, cell implantations, gene editing, and RNA‐ or protein‐based inhibitors. Thus, Clinical and Translational Discovery sincerely welcome you to join and share the rapid development and future successes to come.

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Structure and mechanism of blood–brain-barrier lipid transporter MFSD2A

Cited by 59 publications

References 58 publications

Wnt Signaling in Inner Blood–Retinal Barrier Maintenance

Wnt Signaling in Inner Blood–Retinal Barrier Maintenance

The blood-brain barrier in health, neurological diseases, and COVID-19

Discovery in clinical and translational medicine

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