Abstract
Major facilitator superfamily-domain containing 2a (Mfsd2a) is selectively expressed in vascular endotheliocytes and plays a crucial role in maintaining the integrity of the blood‒brain barrier and the transport of docosahexaenoic acid. It is currently recognized as the only molecule that inhibits endocytosis mediated by caveolae in brain endothelial cells. Mfsd2a gene knockout leads to an increase in the permeability of the blood–brain barrier from embryonic stages to adulthood while maintaining the normal pattern of the vascular network. In Mfsd2a knockout mice, the docosahexaenoic acid content is significantly reduced and associated with neuron loss, resulting in microcephaly and cognitive impairment. Based on the role of Mfsd2a in the central nervous system, it has been preliminarily suggested as a potential therapeutic target for drug delivery to the central nervous system. This paper reviews the current progress in Mfsd2a research and summarizes the physiological functions of Mfsd2a in the central nervous system and its role in the occurrence and development of a variety of neurological diseases.
Graphical Abstract
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data Availability
Not applicable.
Code Availability
Not applicable.
References
Alakbarzade V, Hameed A, Quek DQ, Chioza BA, Baple EL, Cazenave-Gassiot A, Nguyen LN, Wenk MR, Ahmad AQ, Sreekantan-Nair A, Weedon MN, Rich P, Patton MA, Warner TT, Silver DL, Crosby AH (2015) A partially inactivating mutation in the sodium-dependent lysophosphatidylcholine transporter MFSD2A causes a non-lethal microcephaly syndrome. Nat Genet 47(7):814–817. https://doi.org/10.1038/ng.3313
Andreone BJ, Chow BW, Tata A, Lacoste B, Ben-Zvi A, Bullock K, Deik A, Ginty DD, Clish CB, Gu C (2017) Blood–brain barrier permeability is regulated by lipid transport-dependent suppression of caveolae-mediated transcytosis. Neuron 94:581-594.e5. https://doi.org/10.1016/j.neuron.2017.03.043
Angers M, Uldry M, Kong D, Gimble JM, Jetten AM (2008) Mfsd2a encodes a novel major facilitator superfamily domain-containing protein highly induced in brown adipose tissue during fasting and adaptive thermogenesis. Biochem J 416(3):347–355. https://doi.org/10.1042/BJ20080165
Balakrishnan J, Kannan S, Govindasamy A (2021) Structured form of DHA prevents neurodegenerative disorders: a better insight into the pathophysiology and the mechanism of DHA transport to the brain. Nutr Res 85:119–134. https://doi.org/10.1016/j.nutres.2020.12.003
Ben-Zvi A, Lacoste B, Kur E, Andreone BJ, Mayshar Y, Yan H, Gu C (2014) MFSD2A is critical for the formation and function of the blood–brain barrier. Nature 509(7501):507–511. https://doi.org/10.1038/nature13324
Cater RJ, Chua GL, Erramilli SK, Keener JE, Choy BC, Tokarz P, Chin CF, Quek DQY, Kloss B, Pepe JG, Parisi G, Wong BH, Clarke OB, Marty MT, Kossiakoff AA, Khelashvili G, Silver DL, Mancia F (2021) Structural basis of omega-3 fatty acid transport across the blood–brain barrier. Nature 595(7866):315–319. https://doi.org/10.1038/s41586-021-03650-9
Chen H, Tang X, Li J, Hu B, Yang W, Zhan M, Ma T, Xu S (2022) IL-17 crosses the blood–brain barrier to trigger neuroinflammation: a novel mechanism in nitroglycerin-induced chronic migraine. J Headache Pain 23(1):1. https://doi.org/10.1186/s10194-021-01374-9
Colombo F, Falvella FS, Galvan A, Frullanti E, Kunitoh H, Ushijima T, Dragani TA (2011) A 5′-region polymorphism modulates promoter activity of the tumor suppressor gene MFSD2A. Mol Cancer 10:81. https://doi.org/10.1186/1476-4598-10-81
Cui Y, Wang Y, Song X, Ning H, Zhang Y, Teng Y, Wang J, Yang X (2021) Brain endothelial PTEN/AKT/NEDD4-2/MFSD2A axis regulates blood–brain barrier permeability. Cell Rep 36(1):109327. https://doi.org/10.1016/j.celrep.2021.109327
De Bock M, Van Haver V, Vandenbroucke RE, Decrock E, Wang N, Leybaert L (2016) Into rather unexplored terrain transcellular transport across the blood–brain barrier. Glia 64(7):1097–1123. https://doi.org/10.1002/glia.22960
DosSantos MF, Holanda-Afonso RC, Lima RL, DaSilva AF, Moura-Neto V (2014) The role of the blood–brain barrier in the development and treatment of migraine and other pain disorders. Front Cell Neurosci 8:302. https://doi.org/10.3389/fncel.2014.00302
Eser Ocak P, Ocak U, Sherchan P, Gamdzyk M, Tang J, Zhang JH (2020a) Overexpression of Mfsd2a attenuates blood brain barrier dysfunction via Cav-1/Keap-1/Nrf-2/HO-1 pathway in a rat model of surgical brain injury. Exp Neurol 326:113203. https://doi.org/10.1016/j.expneurol.2020.113203
Eser Ocak P, Ocak U, Sherchan P, Zhang JH, Tang J (2020b) Insights into major facilitator superfamily domain-containing protein-2a (Mfsd2a) in physiology and pathophysiology. What do we know so far? J Neurosci Res 98(1):29–41. https://doi.org/10.1002/jnr.24327
Freund LY, Vedin I, Cederholm T, Basun H, Faxén IG, Eriksdotter M, Hjorth E, Schultzberg M, Vessby B, Wahlund LO, Salem N, Palmblad J (2014) Transfer of omega-3 fatty acids across the blood–brain barrier after dietary supplementation with a docosahexaenoic acid-rich omega-3 fatty acid preparation in patients with Alzheimer’s disease: the Omeg AD study. J Intern Med 275(4):428–436. https://doi.org/10.1111/joim.12166
Guemez-Gamboa A, Nguyen LN, Yang H, Zaki MS, Kara M, Ben-Omran T, Akizu N, Rosti RO, Rosti B, Scott E, Schroth J, Copeland B, Vaux KK, Cazenave-Gassiot A, Quek DQ, Wong BH, Tan BC, Wenk MR, Gunel M, Gabriel S, Chi NC, Silver DL, Gleeson JG (2015) Inactivating mutations in MFSD2A, required for omega-3 fatty acid transport in brain, cause a lethal microcephaly syndrome. Nat Genet 47(7):809–813. https://doi.org/10.1038/ng.3311
Harel T, Quek DQY, Wong BH, Cazenave-Gassiot A, Wenk MR, Fan H, Berger I, Shmueli D, Shaag A, Silver DL, Elpeleg O, Edvardson S (2018) Homozygous mutation in MFSD2A, encoding a lysolipid transporter for docosahexanoic acid, is associated with microcephaly and hypomyelination. Neurogenetics 19(4):227–235. https://doi.org/10.1007/s10048-018-0556-6
Ju X, Miao T, Chen H, Ni J, Han L (2021) Overcoming Mfsd2a-mediated low transcytosis to boost nanoparticle delivery to brain for chemotherapy of brain metastases. Adv Healthc Mater 10(9):e2001997. https://doi.org/10.1002/adhm.202001997
Kempińska W, Korta K, Marchaj M, Paprocka J (2022) Microcephaly in neurometabolic diseases. Children (basel). 9(1):97. https://doi.org/10.3390/children9010097
Khuller K, Yigit G, Grijalva CM, Altmüller J, Thiele H, Nürnberg P et al (2021) MFSD2A-associated primary microcephaly—Expanding the clinical and mutational spectrum of this ultra-rare disease. Eur J Med Genet 64(10):104310. https://doi.org/10.1016/j.ejmg.2021.104310
Kim YS, Kim M, Choi SH, You SH, Yoo RE, Kang KM, Yun TJ, Lee ST, Moon J, Shin YW (2019) Altered vascular permeability in migraine-associated brain regions: evaluation with dynamic contrast-enhanced MRI. Radiology 292(3):713–720. https://doi.org/10.1148/radiol.2019182566
Kristofova M, Ori A, Wang ZQ (2022) Multifaceted microcephaly-related gene MCPH1. Cells 11(2):275. https://doi.org/10.3390/cells11020275
Liang H, Chen J (2021) Evolution of blood–brain barrier in brain diseases and related systemic nanoscale brain-targeting drug delivery strategies. Acta Pharm Sin B 11(8):2306–2325. https://doi.org/10.1016/j.apsb.2020.11.023
Matuszyk MM, Garwood CJ, Ferraiuolo L, Simpson JE, Staniforth RA, Wharton SB (2022) Biological and methodological complexities of beta-amyloid peptide: implications for Alzheimer’s disease research. J Neurochem 160(4):434–453. https://doi.org/10.1111/jnc.15538
Milanovic D, Petrovic S, Brkic M, Avramovic V, Perovic M, Ivkovic S, Glibetic M, Kanazir S (2018) Short-term fish oil treatment changes the composition of phospholipids while not affecting the expression of Mfsd2a omega-3 transporter in the brain and liver of the 5xFAD mouse model of Alzheimer’s disease. Nutrients 10(9):1250. https://doi.org/10.3390/nu10091250
Naveed M, Kazmi SK, Amin M, Asif Z, Islam U, Shahid K, Tehreem S (2018) Comprehensive review on the molecular genetics of autosomal recessive primary microcephaly (MCPH). Genet Res (camb) 100:e7. https://doi.org/10.1017/S0016672318000046
Nguyen LN, Ma D, Shui G, Wong P, Cazenave-Gassiot A, Zhang X, Wenk MR, Goh ELK, Silver DL (2014) Mfsd2a is a transporter for the essential omega-3 fatty acid docosahexaenoic acid. Nature 509:503–506. https://doi.org/10.1038/nature13241
Park YH, Shin SJ, Kim HS, Hong SB, Kim S, Nam Y, Kim JJ, Lim K, Kim JS, Kim JI, Jeon SG, Moon M (2020) Omega-3 fatty acid-type docosahexaenoic acid protects against Aβ-mediated mitochondrial deficits and pathomechanisms in Alzheimer’s disease-related animal model. Int J Mol Sci 21(11):3879. https://doi.org/10.3390/ijms21113879
Phan TP, Holland AJ (2021) Time is of the essence: the molecular mechanisms of primary microcephaly. Genes Dev 35:1551–1578. https://doi.org/10.1101/gad.348866.121
Qu C, Song H, Shen J, Xu L, Li Y, Qu C, Li T, Zhang J (2020) Mfsd2a reverses spatial learning and memory impairment caused by chronic cerebral hypoperfusion via protection of the blood–brain barrier. Front Neurosci 14:461. https://doi.org/10.3389/fnins.2020.00461
Razmara E, Azimi H, Tavasoli AR, Fallahi E, Sheida SV, Eidi M, Bitaraf A, Farjami Z, Daneshmand MA, Garshasbi M (2020) Novel neuroclinical findings of autosomal recessive primary microcephaly 15 in a consanguineous Iranian family. Eur J Med Genet 63(12):104096. https://doi.org/10.1016/j.ejmg.2020.104096
Sánchez-Campillo M, Ruiz-Palacios M, Ruiz-Alcaraz AJ, Prieto-Sánchez MT, Blanco-Carnero JE, Zornoza M, Ruiz-Pastor MJ, Demmelmair H, Sánchez-Solís M, Koletzko B, Larqué E (2020a) Child head circumference and placental MFSD2a expression are associated to the level of MFSD2a in maternal blood during pregnancy. Front Endocrinol (lausanne) 11:38. https://doi.org/10.3389/fendo.2020.00038
Sánchez-Campillo M, Ruiz-Pastor MJ, Gázquez A, Marín-Muñoz J, Noguera-Perea F, Ruiz-Alcaraz AJ, Manzanares-Sánchez S, Antúnez C, Larqué E (2020b) Decreased blood level of MFSD2a as a potential biomarker of Alzheimer’s disease. Int J Mol Sci 21(1):70. https://doi.org/10.3390/ijms21010070
Scala M, Chua GL, Chin CF, Alsaif HS, Borovikov A, Riazuddin S, Riazuddin S, Chiara Manzini M, Severino M, Kuk A, Fan H, Jamshidi Y, Toosi MB, Doosti M, Karimiani EG, Salpietro V, Dadali E, Baydakova G, Konovalov F, Lozier E, O’Connor E, Sabr Y, Alfaifi A, Ashrafzadeh F, Striano P, Zara F, Alkuraya FS, Houlden H, Maroofian R, Silver DL (2020) Biallelic MFSD2A variants associated with congenital microcephaly, developmental delay, and recognizable neuroimaging features. Eur J Hum Genet 28(11):1509–1519. https://doi.org/10.1038/s41431-020-0669-x
Semba RD (2020) Perspective: the potential role of circulating lysophosphatidylcholine in neuroprotection against Alzheimer disease. Adv Nutr 11(4):760–772. https://doi.org/10.1093/advances/nmaa024
Shi X, Huang Y, Wang H, Zheng W, Chen S (2018) MFSD2A expression predicts better prognosis in gastric cancer. Biochem Biophys Res Commun 505(3):699–704. https://doi.org/10.1016/j.bbrc.2018.09.156
Spinola M, Falvella FS, Colombo F, Sullivan JP, Shames DS, Girard L, Spessotto P, Minna JD, Dragani TA (2010) MFSD2A is a novel lung tumor suppressor gene modulating cell cycle and matrix attachment. Mol Cancer 9:62. https://doi.org/10.1186/1476-4598-9-62
Teng E, Taylor K, Bilousova T, Weiland D, Pham T, Zuo X, Yang F, Chen PP, Glabe CG, Takacs A, Hoffman DR, Frautschy SA, Cole GM (2015) Dietary DHA supplementation in an APP/PS1 transgenic rat model of AD reduces behavioral and Aβ pathology and modulates Aβ oligomerization. Neurobiol Dis 82:552–560. https://doi.org/10.1016/j.nbd.2015.09.002
Tiwary S, Morales JE, Kwiatkowski SC, Lang FF, Rao G, McCarty JH (2018) Metastatic brain tumors disrupt the blood–brain barrier and alter lipid metabolism by inhibiting expression of the endothelial cell fatty acid transporter Mfsd2a. Sci Rep 8(1):8267. https://doi.org/10.1038/s41598-018-26636-6
Wang JZ, Xiao N, Zhang YZ, Zhao CX, Guo XH, Lu LM (2016) Mfsd2a-based pharmacological strategies for drug delivery across the blood–brain barrier. Pharmacol Res 104:124–131. https://doi.org/10.1016/j.phrs.2015.12.024
Wang Z, Zheng Y, Wang F, Zhong J, Zhao T, Xie Q, Zhu T, Ma F, Tang Q, Zhou B, Zhu J (2020) Mfsd2a and Spns2 are essential for sphingosine-1-phosphate transport in the formation and maintenance of the blood–brain barrier. Sci Adv 6(22):eaay8627. https://doi.org/10.1126/sciadv.aay8627
Wei J, Qin L, Fu Y, Dai Y, Wen Y, Xu S (2022) Long-term consumption of alcohol exacerbates neural lesions by destroying the functional integrity of the blood–brain barrier. Drug Chem Toxicol 45(1):231–238. https://doi.org/10.1080/01480545.2019.1681444
Wood CAP, Zhang J, Aydin D, Xu Y, Andreone BJ, Langen UH, Dror RO, Gu C, Feng L (2021) Structure and mechanism of blood–brain-barrier lipid transporter MFSD2A. Nature 596(7872):444–448. https://doi.org/10.1038/s41586-021-03782-y
Xing S, Kan J, Su A, Liu QD, Wang K, Cai X, Dong J (2019) The prognostic value of major facilitator superfamily domain-containing protein 2A in patients with hepatocellular carcinoma. Aging (albany NY) 11(19):8474–8483. https://doi.org/10.18632/aging.102333
Yang YR, Xiong XY, Liu J, Wu LR, Zhong Q, Zhou K, Meng ZY, Liu L, Wang FX, Gong QW, Liao MF, Duan CM, Li J, Yang MH, Zhang Q, Gong CX, Yang QW (2017) Mfsd2a (Major Facilitator Superfamily Domain Containing 2a) attenuates intracerebral hemorrhage-induced blood–brain barrier disruption by inhibiting vesicular transcytosis. J Am Heart Assoc 6(7):e005811. https://doi.org/10.1161/JAHA.117.005811
Yuan S, Li H, Yang C, Xie W, Wang Y, Zhang J, Cai Z, Mao Z, Xie W, Lü T (2020) DHA attenuates Aβ-induced necroptosis through the RIPK1/RIPK3 signaling pathway in THP-1 monocytes. Biomed Pharmacother 126:110102. https://doi.org/10.1016/j.biopha.2020.110102
Zaqout S, Kaindl AM (2022) Autosomal recessive primary microcephaly: not just a small brain. Front Cell Dev Biol 9:784700. https://doi.org/10.3389/fcell.2021.784700
Zhang XP, Liu YR, Chai M, Yang HT, Wang G, Han M, Li DB (2019) High-fat treatment prevents postoperative cognitive dysfunction in a hyperlipidemia model by protecting the blood–brain barrier via Mfsd2a-related signaling. Mol Med Rep 20(5):4226–4234. https://doi.org/10.3892/mmr.2019.10675
Zhao Z, Zlokovic BV (2014) Blood–brain barrier: a dual life of MFSD2A? Neuron 82(4):728–730. https://doi.org/10.1016/j.neuron.2014.05.012
Zhao C, Ma J, Wang Z, Li H, Shen H, Li X, Chen G (2020a) Mfsd2a attenuates blood–brain barrier disruption after sub-arachnoid hemorrhage by inhibiting caveolae-mediated transcellular transport in rats. Transl Stroke Res 11(5):1012–1027. https://doi.org/10.1007/s12975-019-00775-y
Zhao Y, Long Z, Ding Y, Jiang T, Liu J, Li Y, Liu Y, Peng X, Wang K, Feng M, He G (2020b) Dihydroartemisinin ameliorates learning and memory in Alzheimer’s disease through promoting autophagosome-lysosome fusion and autolysosomal degradation for Aβ clearance. Front Aging Neurosci 12:47. https://doi.org/10.3389/fnagi.2020.00047
Zhou J, Chi X, Cheng M, Huang X, Liu X, Fan J, Xu H, Lin T, Shi L, Qin C, Yang W (2019) Zika virus degrades the ω-3 fatty acid transporter Mfsd2a in brain microvascular endothelial cells and impairs lipid homeostasis. Sci Adv 5(10):7142. https://doi.org/10.1126/sciadv.aax7142
Acknowledgements
None.
Funding
No.
Author information
Authors and Affiliations
Contributions
YZ contributed to literature search, ZH contributed to literature reading and article writing, and JS contributed to article modification and submission.
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Ethical Approval
Not applicable.
Consent to Participate
Not applicable.
Consent for Publication
All the author confirm that the work has not been submitted elsewhere for publication, in whole or in part, and that its publication has been approved by all co-authors.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
He, Z., Zhao, Y. & Sun, J. The Role of Major Facilitator Superfamily Domain-Containing 2a in the Central Nervous System. Cell Mol Neurobiol 43, 639–647 (2023). https://doi.org/10.1007/s10571-022-01222-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10571-022-01222-7