ATP-binding cassette transporters as possible targets for the intervention of neurodegenerative diseases

Hiu Chuen Lok,Glenda M.Halliday,Woojin Scott Kim

ATP-binding cassette (ABC) transporters are ubiquitous membrane-bound proteins that are responsible for the translocation of a broad spectrum of substrates across cellular membranes,including lipids,amino acids,nucleosides,sugars,and xenobiotics.Interestingly,ABC transporters are highly expressed in the brain.While their functions in the brain still need to be elucidated,several members are implicated in the pathogenesis of neurodegenerative diseases,including Alzheimer’s disease (AD),Parkinson’s disease (PD),and frontotemporal dementia.In this perspective,we will review current knowledge of ABC transporters in the central nervous system in terms of physiological functions and pathology in neurodegeneration.Furthermore,we will explore the possibilities of ABC transporters as potential targets in the development of therapeutics for neurodegenerative diseases.

ABC transporters constitute one of the largest groups of transporter families in humans,consisting of 49 proteins classified into seven subfamilies,ABCA,ABCB,ABCC,ABCD,ABCE,ABCF,and ABCG (according to the Human Genome Organization),based on sequence homology,size,domain arrangement,and phylogenetic relationships.These ATP-dependent transporters are known to translocate a wide range of substrates across membranes,including amino acids,cyclic nucleotides,nucleosides,lipids,peptides,vitamins,metals,inorganic ions,sugars,and xenobiotics (Katzeff and Kim,2021;Pahnke et al.,2021;Figure 1).ABC transporters are ubiquitously expressed in mammalian cellular membranes including the plasma membrane and intracellular membranes of endosomes,lysosomes,peroxisomes,multivesicular bodies,mitochondria,endoplasmic reticulum,and Golgi (Katzeffand Kim,2021).

Figure 1｜A pictorial model of ABCA transporter prototype.

ABC transporters are highly expressed in the brain,an extremely lipid-enriched tissue.Thus,tight regulation of lipid metabolism and transport is critical for normal neuronal function.Given the role of ABC transporters in lipid metabolism,it is not surprising that these transporters are increasingly recognized for their involvement in metabolic and pathophysiological processes that underlie neurodegenerative diseases (Table 1),a group of diseases characterized by degeneration of neurons and protein aggregation (Pahnke et al.,2021;Moore et al.,2023).Indeed,a number of ABC transporters have been associated with AD in the generation and clearance of amyloid-beta (Aβ) in the central nervous system (CNS) (Pahnke et al.,2021;Namasivayam et al.,2022).The functions and pathophysiology of these transporters in the brain will be discussed in greater detail below.

Table 1｜ATP-binding cassette (ABC) transporters and their putative function in the central nervous system (CNS)

ABCA transporters:ABCA transporters consist of 12 members (ABCA1-13,with ABCA11 being a pseudogene) and are primarily associated with lipid efflux and cholesterol trafficking,and the transport of retinoids.ABCA1 is a cholesterol and phosphatidylcholine transporter and is critical for brain function as it loads newly synthesized cholesterol from astrocytes onto apoE/apoA-1 to transport cholesterol to neurons and myelin (Katzeff and Kim,2021;Pahnke et al.,2021).Of interest,ABCA1-mediated cholesterol efflux capacity is reduced in the cerebral spinal fluid of AD patients (Pahnke et al.,2021).Furthermore,ABCA1 and ABCA2 are responsible for the modulation of sphingosine levels and the transcription of amyloid precursor protein (Pahnke et al.,2021).ABCA5 is implicated as a sphingomyelin transporter (Kim and Halliday,2012) and is associated with PD (Simon-Sanchez et al.,2009).ABCA8 stimulates sphingomyelin production in oligodendrocytesin vitro(Kim et al.,2013) and is implicated in myelination (Liu et al.,2022).Furthermore,the expression of ABCA8 is increased in multiple system atrophy brains (Bleasel et al.,2013).ABCA13 is involved in cellular cholesterol trafficking and the loss of this function is associated with psychiatric disorders (Nakato et al.,2021).

Dysregulation of the expression of ABCA transporters is associated with various neurodegenerative diseases (Katzeff and Kim,2021).Gene variants of ABCA1 and ABCA2 are associated with an increased risk of AD (Katzeffand Kim,2021;Pahnke et al.,2021),while ABCA7 is a genetic risk factor for AD (Steinberg et al.,2015) and PD (Nuytemans et al.,2016).Recently,the expression levels of ABCA2,ABCA3,ABCA4,ABCA7,ABCA9,ABCA10,and ABCA13 were found to be altered in the brains of frontotemporal dementia patients,and these changes in expression were associated with neuroinflammation (Katzeff et al.,2022).Since neuroinflammation is a hallmark of neurodegeneration,these findings would have broader implications for understanding the pathogenesis of neurodegenerative diseases.

ABCB transporters:ABCB transporter subfamily is comprised of 11 members with ABCB1 being the most well-characterized.ABCB1,also known as p-glycoprotein or multidrug resistance protein 1,is primarily responsible for the efflux of xenobiotics.In the brain,ABCB1 is expressed in microglia,neurons,astrocytes,pericytes,endothelial cells,and choroid plexus.ABCB1,ABCB2,ABCB3,and ABCB10 are implicated in neurodegenerative diseases.ABCB1 is considered to be a rare risk factor for PD,and its expression is altered in the brains of patients with AD and amyotrophic lateral sclerosis (Katzeff and Kim,2021).Interestingly,ABCB1 is thought to act as a gatekeeper for the peripheral entry of Aβ into the cerebral spinal fluid.ABCB1 interacts directly with Aβ to mediate its efflux across the blood-brain barrier (Namasivayam et al.,2022).Indeed,loss-offunction of ABCB1 increases CNS Aβ levels,while pharmacological upregulation of ABCB1 leads to enhanced cerebral clearance of Aβ in mouse models of AD (Namasivayam et al.,2022;Moore et al.,2023).ABCB2 and ABCB3 are implicated in PD,with the expression of both transporters elevated in mouse models of PD and in PD brain tissue (Moore et al.,2023).In addition,downregulation of ABCB10 is also reported in a mouse model of Huntington’s disease and in fibroblast cell lines derived from Huntington’s disease patients (Moore et al.,2023).

ABCC transporters:There are 12 members in the ABCC transporter subfamily,of which ABCC1 is the most well-known.Due to their ability to efflux a wide range of chemotherapeutic drugs,ABCC transporters are also known as multidrug resistance-associated proteins.In the brain,ABCC1 is present in microglia,neurons,astrocytes,pericytes,and basal membrane (Katzeffand Kim,2021).While the exact function of ABCC1 in the brain remains to be elucidated,evidence suggests that ABCC1 is involved in the clearance of Aβ (Namasivayam et al.,2022),and that increases in ABCC1 expressionin vitrolead to decreases in extracellular Aβ.Furthermore,ABCC1-deficient mice have elevated Aβ levels,while overexpression of ABCC1 results in reduced Aβ load in a mouse model of AD (Moore et al.,2023).

ABCG transporters:The five-membered ABCG transporter subfamily is responsible for the transport of lipids,e.g.,cholesterol.In addition,ABCG2 is also known as breast cancer resistance protein because of its ability to induce drug resistance in cancer cells through the efflux of chemotherapeutic agents.In the brain,ABCG2 is expressed in neurons,astrocytes,microglia,pericytes,and brain epithelium (Katzeffand Kim,2021).While very little is known about ABCG transporters in neurodegenerative diseases,ABCG1 variants are associated with AD risk (Moore et al.,2023) and ABCG2 is implicated in AD,PD,and amyotrophic lateral sclerosis (Katzeff and Kim,2021).The ABCG2 variant C421A has been reported to be a risk factor for AD,while Q141K delays the onset of PD (Katzeffand Kim,2021).The expression of ABCG2 is elevated in the spinal cord and motor cortex of both familial and sporadic cases of amyotrophic lateral sclerosis (Katzeffand Kim,2021).Furthermore,ABCG2 interacts directly with Aβ and is a gatekeeper for peripheral Aβ entry into the CNS (Namasivayam et al.,2022).In addition,ABCG1 and ABCG4 were suggested to suppress Aβ secretion (Katzeffand Kim,2021).Indeed,ABCG1 knockout mice display higher levels of Aβ in the CNS (Moore et al.,2023).

ABC transporters as novel targets for the intervention of neurodegenerative diseases:An improved understanding of the roles of ABC transporters in brain function could lead to new strategies in the development of therapeutics for neurodegenerative diseases.Their roles in lipid and Aβ transport make these transporters attractive targets for pharmaceutical and genetic manipulation,which could lead to attenuation or clearance of Aβ.One such example is the use of agonists for the transcription factor liver X receptor,which regulates ABCA1 transcription.Activation of liver X receptor,by the liver X receptor agonists GW3965 and T0901317,therefore increases ABCA1 expression,reduces amyloid precursor protein processing and Aβ secretion,and improves cognition in AD mouse models.Therefore,induction of the ABCA1 function has been proposed as a therapeutic strategy for AD (Bossaerts et al.,2022).

Another strategy that has been explored therapeutically is the use of activators of ABC transporters that promote the binding and/or translocation of Aβ (Namasivayam et al.,2022).As mentioned earlier,several members of the ABC transporter family (e.g.,ABCB1,ABCC1,and ABCG2) interact directly with Aβ and increase the clearance of Aβ across the blood-brain barrier into the bloodstream (Namasivayam et al.,2022).Indeed,it has been shown that overexpression of ABCC1 in mice has led to lower Aβ load (Moore et al.,2023),and thus compounds that can increase ABC transporter activity to facilitate more effective Aβ clearance are certainly therapeutics worthy of further investigation.

In conclusion,further research is required to improve the current knowledge of the roles of ABC transporters in the brain considering their potential to lead to novel strategies for treating neurodegenerative diseases.

Hiu Chuen Lok,Glenda M.Halliday,Woojin Scott Kim*

Brain and Mind Centre &School of Medical Sciences,The University of Sydney,Sydney,NSW,Australia

*Correspondence to:Woojin Scott Kim,PhD,woojin.kim@sydney.edu.au.

https://orcid.org/0000-0002-4707-933X(Woojin Scott Kim)

Date of submission:May 3,2023

Date of decision:June 25,2023

Date of acceptance:July 7,2023

Date of web publication:September 4,2023

https://doi.org/10.4103/1673-5374.382239

How to cite this article:Lok HC,Halliday GM,Kim WS (2024) ATP-binding cassette transporters as possible targets for the intervention of neurodegenerative diseases.Neural Regen Res 19(4):721-722.

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