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  • There is a growing literature on

    2024-05-14

    There is a growing literature on ABCA2 expression in human biopsies, where it has been described as a potential biomarker of leukemias. In childhood T-cell acute lymphoblastic leukemia, ABCA2 and ABCA3 were expressed at high levels, which upon treatment with methotrexate, vinblastine and doxorubicin were amplified further [38], implying a function in resistance. Since normal pkc inhibitors and bone marrow express high levels, it is unsurprising that greater abundance occurs in their neoplastic counterparts. Specifically, high expression occurs in vestibular schwannomas, a benign intracranial tumor originating from a branch of the acoustic nerve in the PNS [17]. ABCA2 was abundant in histologically defined Antoni type A and type B areas of the biopsies [17]. The transporter was also shown in oligodendrogliomas of the CNS [40], where it outperformed Olig2 as a biomarker for oligodendrogliomas from astrocytic tumors. Most recently, within a group of ALL patients, quantification of the protein levels of ABCA2 and ABCA3 had a prognostic impact on pediatric ALL MDR. These authors deduced the tertiary structure of ABCA2 and using docking analysis revealed a possible compensatory effect between ABCA2 and ABCA3, which they thought might contribute to drug efflux and ultimately, to chemoresistance [41].
    ABCA2 knockout studies/phenotypes Two groups have independently generated ABCA2 knockout mice [19], [42]. Our own and Sakai et al. observed a distinct shaking phenotype particularly affecting the hind limbs, that we termed “Skittish”. While in general the mouse phenotypes were very similar, there were some apparent differences in myelin sheath morphology and in brain lipid profiles. Our group reported that mice displayed tremor, hyperactivity and abnormal myelin ultrastructure, i.e., compaction of the myelin sheath in the brain and spinal cord that we proposed was the cause of the tremor. In contrast, the Sakai group did not observe abnormalities in the cytoarchitectonic and compact myelin structure or oligodendroglia differentiation. Analysis of brain lipids of mice aged 11 days to 14 weeks revealed differences in the sphingolipid profile. They reported age-related deficiencies in the brains of phosphatidylethanolamine (PE) and phosphatidylserine (PS), sphingomyelin (SM) and a significant (twofold) accumulation of ganglioside GM1 in ABCA2 knockout mice compared to wild-type littermates. Similar results were obtained in the myelin fraction of ABCA2-null brain. They proposed that ABCA2 functions to modulate the intracellular metabolism of sphingolipids in the brain. These results provide additional evidence in vivo that ABCA2 is a key molecule that regulates sphingolipid homeostasis. The appearance of the skittish phenotype prevented the extension of any further cancer related work on the transporter and instead altered focus onto neurological pathologies. Given the extreme nature of the knockout mouse tremors, it would appear that there may be added opportunities for further research with this model.
    Rationale for studying the endogenous function of ABCA2 Our rationale for studying the endogenous function of ABCA2 in cells involved a consideration of the similarity between its DNA sequence and predicted protein structure compared to ABCA1. ABCA1 is the key molecule involved in reverse cholesterol transport (RCT) [43]. We hypothesized that ABCA2 was also a key molecule in maintaining intracellular cholesterol homeostasis. However, the subcellular distribution of ABCA1 and ABCA2 differ significantly; whereas ABCA1 is predominantly localized to the plasma membrane compartment [44], ABCA2 is predominantly localized in the late-endosome/lysosomal membrane compartment (LE/LY) [12], [45]. The LE/LY is the terminal endocytic compartment where free cholesterol, liberated from cholesteryl ester molecules contained in low-density lipoprotein (LDL) particles by acid lipase, is distributed to other intracellular compartments in a highly regulated process. This difference in subcellular localization suggested fundamental differences in the roles of ABCA1 and ABCA2 in maintaining intracellular cholesterol homeostasis.