Oligodendrocytes constitute a large percentage of glial
cells in the central nervous system (CNS) dedicated to the maintenance of
neuronal function. They produce myelin, an insulating complex that enhances the
saltatory propagation of action potentials and the speed of neural processing.
The risk for developing neurodegenerative diseases is inversely correlated with
the progressive decline of myelin in the aging brain (Bartzokis, Beckson &
Lu et al., 2001). A hallmark of age-related neurodegenerative diseases is the
progressive and widespread axonal and neuronal cell loss within the CNS (Ettle,
Schlachetzki & Winkler, 2015). In multiple system atrophy (MSA), the pathological
sequence of events leading to neuronal death begins with abnormal
redistribution of myelin proteins in oligodendrocytes, followed by myelin
dysfunction, neurodegeneration, and the loss of neurons (Wong, Halliday &
Kim, 2014). Neuropathological changes observed in MSA brains include myelin
loss, alongside neuro- and axonal degeneration (Wenning, Stefanova &
Jellinger et al., 2008), suggesting that neuronal death may be caused by the
impairment and loss of myelin.


Specific assembly of myelin-related proteins and lipids in membrane

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CNS myelin is characterised by a higher
proportion of lipids to proteins than most other biological membranes (Brady et al., 2005). The most abundant lipids enriching myelin are
cholesterol and phospholipids, the characteristic phospholipids
being ethanolamine plasmalogens (Morrell and Quarles, 1999). In contrast,
glycosphingolipids like sphingomyelin (SM) constitute a minor proportion of the
total lipid content. The major CNS myelin protein constituents are proteolipid
proteins (PLP) and myelin basic proteins (MBP). Though present to a lesser
extent, 2′,3′-cyclic-nucleotide 3′-phosphodiesterases (CNP) and
myelin-oligodendrocyte glycoproteins (MOG) are still detectable biochemical
markers for myelinating cells. Oligodendrocyte precursor cells (OPCs) actively
proliferate as they migrate throughout
the CNS. They stop proliferating to differentiate into mature oligodendrocytes
to facilitate myelination. Neurons
release ATP from axons firing action potentials to stimulate astroglial cells
(Ishibashi et al., 2006). Activated astroglial cells release the cytokine
leukemia inhibitory factor (LIF), to promote myelination of axons by
mature oligodendrocytes (Ishibashi et al., 2006) and to restore
oligodendrocytes from induced acute demyelination (Deverman and Patterson,
2012). In rats, the synthesis of myelin components by OPCs occurs post-natally,
at about 10-12 days of age. Post-synthesis, myelin components are sorted and
transported to various domains in the membrane for selective integration. When
cross-sectioned, myelin appears as specialised
extensions of the oligodendroglial plasma membrane forming spiralled structures
that wrap around axons (Ioannidou, Anderson,
Strachan, Edgar & Barnett, 2012). Lipids enriching myelin are
arranged in highly ordered raft-like microdomains in the membrane with
associated structural and signalling proteins (Lee,
2001). These microdomains are thought to play an important role in
membrane fluidity and permeability, and compartmentalisation of cellular


1.2. Importance of lipid rafts in myelin integrity and


PLP is a structural protein spanning the bilayer of myelin membranes. It
is responsible for maintaining the separation between intra-period lines and
stabilising the ultrastructure of compact myelin (Aggarwal, Yurlova &
Simons, 2011). PLP interacts with lipids, particularly with membrane
microdomain sphingomyelin, cholesterol and plasmalogens, for its transport to
myelin membranes (Wong, Halliday & Kim, 2014). Depletion or inhibition of
these lipid components were shown to reduce PLP-lipid interactions, thereby
impeding PLP transport and downstream compaction of myelin layers (Kramer-Albers,
Gehrig-Burger & Thiele et al., 2006; Simons, Krämer & Thiele et al.,
2000). Lipids in these membrane microdomains also serve a role in important
signalling pathways. Sphingomyelin (SM) is cleaved by sphingomyelinases to form
ceramide, a second messenger for cellular processes regulating cell survival.
In Niemann-Pick disease, sphingomyelin accumulation manifests in irreversible
neurological damage that may or may not be attributed to sphingomyelinase
deficiency (Kolter and Sandhoff, 2006). Given that ATP-binding cassette (ABC) transporters
regulate brain lipid homeostasis, their role in myelination is of particular
interest in this study.


ATP-binding cassette (ABC) transporters


ABC transporters are a superfamily of transmembrane proteins
that bind and hydrolyse ATP to actively translocate a wide variety of
substances across extra- and intracellular membranes (Dean, 2001). ATP
transporters are divided into seven subfamilies, designated A to G, and
classified based on the nucleotide and protein sequence homology, and
organisation of their ATP-binding domains (Dean, 2001). The subfamily A (ABCA)
transporters are characterised by their ability to transport lipids across
membranes and regulate lipid homeostasis in brain and peripheral tissues (Kim,
Weickert & Garner, 2008).


ABCA8 is highly expressed in the white matter of the brain


ABCA8 is a little-known member of the ABCA
family. It was found to be differentially expressed in multiple regions
of the brain with significantly higher expression in oligodendrocyte-enriched
white matter regions compared to grey matter cortical regions (Kim, Hsiao &
Bhatia et al., 2013). The expression of ABCA1 in the same regions were unaltered, suggesting a functional importance
unique to ABCA8 in the brain
(Kim, Hsiao & Bhatia et al., 2013). To validate the significance of this
data, the expression of ABCA8 in the cortex was recorded across the
human lifespan. Only ABCA8 expression was shown to parallel an
age-associated increaseOffice1  in white
matter volume, perhaps owing to an increase in myelination (Kim, Hsiao &
Bhatia et al., 2013). In comparison, the expression of ABCA1 and ABCG1
remained unaltered (Kim, Hsiao & Bhatia et al., 2013).  


1.5. ABCA8 stimulates cholesterol efflux in oligodendrocytes


ABCA1 mediates cholesterol secretion by releasing free
cholesterol onto HDL lipoproteins containing apolipoprotein A-1 (ApoA-1)
present in cerebrospinal fluid. Removal of these lipoproteins from the brain is
regulated by receptors in brain capillary endothelial cells (Zhang & Liu,
2015). To test the role of ABCA8
as a lipid transporter in the brain, a classical lipid efflux assay was
performed in cultured oligodendrocytes. In vitro, ABCA8 was shown to
significantly stimulate cholesterol efflux independent of extracellular ApoA-1
and apolipoprotein E (ApoE). Interestingly, ABCA8 expression was not
inducible by cholesterol metabolism regulators LXR/RXR (liver X
receptor/retinoid X receptor) or PPAR? (peroxisome proliferator-activated
receptor ?) ligand pioglitazone (Kim, Hsiao & Bhatia et al., 2013),
suggesting that gene expression may be regulated by other nuclear receptors or phosphorylation.


1.6. ABCA8 localises to the plasma membrane and endoplasmic
reticulum and facilitates cholesterol efflux to apolipoprotein acceptor, ApoA-1


The role of ABCA8
in cholesterol metabolism and HDL-mediated transport was previously
characterised in the liver. Loss of function mutations in ABCA8 were
linked to low HDL cholesterol (HDLc) levels in the plasma (Trigueros-Motos et
al., 2017). Following this association, its function in cellular cholesterol
transport was evaluated. In Cos-7 cells, wild-type ABCA8 was shown to localise
to the plasma membrane and endoplasmic reticulum (ER). Mutated ABCA8 remained
localised intracellularly in the ER and failed to translocate to the cell
surface (Trigueros-Motos et al., 2017). It was therefore theorised that like ABCA1, ABCA8 may play a role in cholesterol secretion as a
membrane-associated efflux protein. To confirm this, ApoA-1 mediated
cholesterol efflux was assessed in Cos-7 cells transfected with wild-type or
mutated ABCA8. Cells transfected with wild-type ABCA8 showed 181%
increase in cholesterol efflux compared to a 20-43% decrease compared with wild-type
ABCA8 with the mutated gene (Trigueros-Motos et al., 2017).


The ability of ABCA8 to efflux cholesterol suggests that its
function is not compensating for the lower expression of ABCA1 observed
in the brain. Moreover, ABCA8 expression is not inducible by cholesterol
metabolism regulators, indicating a role in lipid homeostasis apart from
cholesterol efflux. Instead, it may modulate lipid transport to intracellular
membranes, indirectly altering lipid concentrations at the plasma membrane.





Plasmalogens may alter the lipid composition of plasma membranes


Given that wild-type ABCA8 is localised both intracellularly
and at the cell surface, it is possible that ABCA8 may facilitate the transport
of cellular ethanolamine plasmalogens to specific membrane microdomains in the
cell. Several findings fit with this possibility. First, decreased cellular
plasmalogen levels were shown to underlie the low HDLc levels observed in ABCA8
heterozygous mutation carriers. Altered transport of internalised cholesterol
(Munn, Arnio & Liu et al., 2003) and abnormal distribution of cellular
cholesterol (Thai, Rodemer & Jauch et al., 2001) were also observed in
cells deficient in plasmalogens. This suggests that cellular plasmalogen levels
modulate the size of plasma membrane cholesterol pools available in the cell.


Membrane cholesterol levels directly influence ?-secretase
activity in Alzheimer’s Disease


The pathological hallmarks of Alzheimer’s disease (AD)
include the deposition of intracellular neurofibrillary tangles and
extracellular amyloid plaques of ?-amyloid
peptides (A?). Under normal physiological
conditions, most amyloid precursor proteins (APP) are cleaved by ?-secretase,
and only a small percentage are cleaved by ?-secretase
to produce pathogenic A? deposits. Since
?-secretase is localised in the phospholipid-rich membrane domain and ?-secretase is localised in the
cholesterol-rich membrane domain, changes in membrane lipid composition were
thought to incite the transition to a predominantly ?-secretase driven
processing of APP that is characteristic of AD (Wood, Goodenowe & Khan et
al., 2011). Consistent with this theory is the finding that neuronal plasma
membranes of AD patients are enriched with cholesterol, which increases with
the progression of the disease (Cutler, Kelly & Storie et al., 2004).
Furthermore, in vitro studies in primary neurons have shown that a
surplus of cholesterol at the plasma membrane results in an increase in A?
deposition (Marquer, Devauges & Cossec et al., 2011). Indeed, increased
membrane cholesterol was shown to elevate ?-secretase activity in HEK293 cells
but no effect on ?-secretase activity was observed (Wood, Goodenowe & Khan
et al., 2011). It is therefore possible that the quantitative manipulation of
constituent lipids in membrane microdomains results in the disorganisation of
its structure and dissociation of non-pathogenic, bound proteins,
thus favouring assimilation
with pathogenic variants, as is the case with AD.


1.9. ABCA8 regulates sphingomyelin metabolism in


expression was altered in cultured oligodendrocytes through overexpression and
knock-down to evaluate its effect on SM production (Kim, Hsiao & Bhatia et
al., 2013). SM production was found to be upregulated in ABCA8 overexpressing cells through a significant increase in sphingomyelin
synthase 1 (SGMS1) expression, not owing to sphingomyelinase
activity (Kim, Hsiao & Bhatia et al., 2013). Furthermore, cells treated
with SM synthesis inhibitors to reduce cellular SM levels were found to
strongly upregulate ABCA8 expression (Kim, Hsiao & Bhatia et al.,
2013), suggesting a role for ABCA8 in SM production. Another study has shown
that SGMS1 is co-expressed with the SGMS2 isoform which is also
known to contribute to sphingomyelin metabolism (Tafesse et al., 2007). They
catalyse the biosynthesis of sphingomyelin by transferring the
phosphorylcholine moiety from phosphatidylcholine to ceramide, forming
sphingomyelin and diacylglycerol. Ceramide is a bioactive lipid that is acted
on by sphingomyelinases to produce a second messenger for important cellular
processes, including apoptosis. Conversely, diacylglycerol activates protein
kinase C to promote cell proliferation. Taken together, it suggests that ABCA8
may increase the production of SGMS-generated sphingomyelin and indirectly
promote cell proliferation by decreasing cellular ceramide and increasing
diacylglycerol concentrations (Yamaoka et al., 2004).

 Office1Inst this decrease as you get older? Or are you trying to say
increase during the early development period?

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