ATP-binding cassette protein ABCA7 deficiency impairs sphingomyelin synthesis, cognitive discrimination, and synaptic plasticity in the entorhinal cortex

Iqbal, Jahangir; Suarez, Manuel D.; Yadav, Pradeep Kumar; Walsh, Meghan T.; Li, Yimeng; Wu, Yiyang; Huang, Zhengwei; James, Antonisamy William; Escobar, Victor; Mokbe, Ashwag; Brickman, Adam M.; Luchsinger, José A.; Dai, Kezhi; Moreno, Herman; Hussain, M. Mahmood

doi:10.1016/j.jbc.2022.102411

Cited by 8 publications

(8 citation statements)

References 51 publications

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“…These cells were then treated with C6-NBD ceramides and incubated with either bovine serum albumin (BSA) to quantify basal efflux ( siCTRL-BSA ) or with human HDL to study their transport to HDL ( siCTRL-HDL ) ( Figure 2 ). HDL significantly increased HexCer efflux when compared to BSA ( Figure 2 A,B) consistent with our previous studies [ 32 , 33 ] that HDL enhances HexCer efflux. We observed that siABCC10 significantly decreased HexCer export to HDL ( Figure 2 A,B).…”

Section: Resultssupporting

confidence: 92%

“…Next, we hypothesized that other unknown proteins exist that play important roles in the export of HexCer. To identify the HexCer transporter(s), we used the approach that we previously undertook to identify ABCA7 as an important regulator of SM biosynthesis and efflux [ 33 ]. Studies to identify the HexCer transporters were performed in parallel with those reported earlier in the identification of SM transporter [ 33 ].…”

Section: Resultsmentioning

confidence: 99%

“…To identify the HexCer transporter(s), we used the approach that we previously undertook to identify ABCA7 as an important regulator of SM biosynthesis and efflux [ 33 ]. Studies to identify the HexCer transporters were performed in parallel with those reported earlier in the identification of SM transporter [ 33 ]. Briefly, we knocked down ABC transporter family members using specific siRNAs in Huh-7 cells.…”

Section: Resultsmentioning

confidence: 99%

“…ABCA1 participates in the efflux of phospholipid and cholesterol [ 46 , 47 ]. We have recently shown that ABCA7 affects synthesis and export of SM and its deficiency in mice affects brain SM metabolism causing cognitive defects [ 33 ]. The current report indicates that ABCC10 plays a role in the synthesis of HexCer.…”

Section: Discussionmentioning

confidence: 99%

“…Human hepatoma Huh-7 cells were reverse transfected with either 50 nM of siCTRL or different concentrations of siABCC10 (12.5, 25, 50, and 100 nM) using RNAiMAX [ 33 ].…”

Section: Methodsmentioning

confidence: 99%

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ATP-Binding Cassette Transporter Family C Protein 10 Participates in the Synthesis and Efflux of Hexosylceramides in Liver Cells

2022

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In addition to sphingomyelin and ceramide, sugar derivatives of ceramides, hexosylceramides (HexCer) are the major circulating sphingolipids. We have shown that silencing of ABCA1 transmembrane protein function for instance in cases of loss of function of ABCA1 gene results in low levels of HDL as well as a concomitant reduction in plasma HexCer levels. However, proteins involved in hepatic synthesis and egress of HexCer from cells is not well known although ABCA1 seems to be indirectly controlling the HexCer plasma levels by supporting HDL synthesis. In this study, we hypothesized that protein(s) other than ABCA1 are involved in the transport of HexCer to HDL. Using an unbiased knockdown approach, we found that ATP-binding cassette transporter protein C10 (ABCC10) participates in the synthesis of HexCer and thereby affects egress to HDL in human hepatoma Huh-7 cells. Furthermore, livers from ABCC10 deficient mice had significantly lower levels of HexCer compared to wild type livers. These studies suggest that ABCC10 partakes in modulating the synthesis and subsequent efflux of HexCer to HDL in liver cells.

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Section: Resultssupporting

confidence: 92%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…Human hepatoma Huh-7 cells were reverse transfected with either 50 nM of siCTRL or different concentrations of siABCC10 (12.5, 25, 50, and 100 nM) using RNAiMAX [ 33 ].…”

Section: Methodsmentioning

confidence: 99%

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ATP-Binding Cassette Transporter Family C Protein 10 Participates in the Synthesis and Efflux of Hexosylceramides in Liver Cells

2022

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Genetic Phenotypes of Alzheimer’s Disease: Mechanisms and Potential Therapy

et al. 2023

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Years of intensive research has brought us extensive knowledge on the genetic and molecular factors involved in Alzheimer's disease (AD). In addition to the mutations in the three main causative genes of familial AD (FAD) including presenilins and amyloid precursor protein genes, studies have identified several genes as the most plausible genes for the onset and progression of FAD, such as triggering receptor expressed on myeloid cells 2, sortilin-related receptor 1, and adenosine triphosphate-binding cassette transporter subfamily A member 7. The apolipoprotein E ε4 allele is reported to be the strongest genetic risk factor for sporadic AD (SAD), and it also plays an important role in FAD. Here, we reviewed recent developments in genetic and molecular studies that contributed to the understanding of the genetic phenotypes of FAD and compared them with SAD. We further reviewed the advancements in AD gene therapy and discussed the future perspectives based on the genetic phenotypes.

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