ABCA2 and Associated Diseases
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Overview of ABCA2
ATP-binding cassette (ABC) transporters are multidomain membrane proteins capable of directed pumping of substrates across cell membranes. As a member of the A sub-family of ABC transporters, ABCA2 is primarily a pleiotropic endolysosomal membrane protein. The expression of ABCA2 can be observed in different types of tissues, especially in the central nervous system and macrophages. In addition, ABCA2 expression is upregulated in human macrophages during cholesterol infusion.
Fig.1 ABCA2 structural organization in the membrane bilayer. (Davis, 2018)
Functions of ABCA2
Located at chromosome 9q34, the ABCA2 gene contains an open reading frame with 2436 amino acids. There is a lipocalin characteristic motif in the sequence of the ABCA2 gene which suggests that ABCA2 plays significant roles in maintaining sterol, sphingolipid, and cholesterol homeostasis. What’s more, ABCA2 also exerts an important role in the transport of low-density lipoprotein (LDL)-derived free cholesterol and is co-expressed with sterol-responsive genes.
Fig.2 Hypothetical model of ABCA2 function in the LE/LY. (Davis, 2018)
ABCA2 Mutation and Associated Human Disease
ABC transporters are essential in the efflux of both endogenous and exogenous substrates. Therefore, the dysfunction of these transporters is closely related to many clinical diseases. Mutations in ABC transporter genes may trigger a variety of human diseases and induce drug resistance in cancer cells. For example, human vestibular schwannoma and ovarian cancer cells expressing high levels of ABCA2 exhibit resistance to multiple compounds, such as mitoxantrone, estradiol, and the free-radical initiator 2,2'-azobis-(2-amidinopropane). Recent studies have shown that the deregulation of ABCA2 might affect cellular phenotypes leading to the pathogenesis of multiple human diseases including Alzheimer's disease (AD), atherosclerosis, and cancer.
Expression levels of ABCA2 are elevated in areas associated with AD pathology, including the temporal and frontal regions of the brain. ABCA2 has recently been shown to affect Aβ production and is therefore considered to be a target for future therapeutic strategies in neurodegenerative diseases. Defects in cholesterol metabolism and LDL regulation have been associated with a variety of cancers including prostate, breast, pancreatic, squamous cell carcinoma, and small cell lung cancer. ABCA2 maintains cholesterol homeostasis and plays an important role in normal and malignant cell proliferation.
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Reference
- Davis, Jr.W.; Tew, K.D. ATP-binding cassette transporter-2 (ABCA2) as a therapeutic target. Biochemical pharmacology. 2018, 151: 188-200.
