Galactolipid-deficient animals:
Among the most abundant components of myelin are the galactolipids
galactocerebroside (GalC) and sulfatide. In spite of this
abundance, the roles that these molecules play in the myelin
sheath are not well understood. Recently, however, genetic
studies have allowed us to re-analyze the functions of these
lipids. Two laboratories 2,3 have independently
generated mice that are incapable of synthesizing either GalC
or sulfatide by inactivating the gene encoding the enzyme
UDP-galactose:ceramide galactosyltransferase (CGT), which
is required for myelin galactolipid synthesis. These galactolipid-
deficient animals exhibit a severe tremor, hindlimb paralysis,
and display electrophysiological deficits in both the central
and peripheral nervous systems. In addition, ultrastructural
studies have revealed hypomyelinated white matter tracts with
unstable myelin sheaths and a variety of myelin abnormalities
including altered node length, reversed lateral loops, and
compromised axo-oligodendrocytic junctions. Collectively,
these observations indicate that cell-cell interactions, which
are essential in the formation and maintenance of a properly
functioning myelin sheath, are compromised in these galactolipid-deficient
mice 4.
Sulfatide inhibits HIV-1 entry into
CD4-/CXCR4+ cells:
Sulfatide (3'-sulfogalactosylceramide)
is the natural sulfated derivative of galactosylceramide
(GalCer), a glycosphingolipid receptor allowing HIV-1 infection
of CD4-negative cells from neural and intestinal tissues.
The incorporation of exogenous sulfatide into the plasma
membrane of HT-29 (a CD4-/GalCer+/CXCR4+ human intestinal
cell line) or RD (CD4-/GalCer-/ CXCR4+ human rhabdomyosarcoma)
resulted in a dose-dependent inhibition of HIV-1 infection
5.
Interaction of Cerebrosides and Cerebroside
Sulfate, Divalent Ion mediated:
Divalent cations mediate a carbohydrate-carbohydrate
association between the two major glycolipids, galactosylceramide
(GalCer) and its sulfated form, cerebroside sulfate (CBS),
of the myelin sheath. It appears that interaction between
these glycolipids on apposed extracellular surfaces of myelin
may be involved in the stability or function of this multilayered
structure. A mutant mouse lacking galactolipids because
of a disruption in the gene that encodes a galactosyltransferase
forms myelin that initially appears relatively normal but
is unstable. This myelin contains glucosylceramide (GlcCer)
instead of GalCer. To better understand the role of GlcCer
in myelin in this mutant, we have compared the ability of
divalent cations to complex CBS (galactosyl form) with GlcCer
or GalCer in methanol solution by using positive ion electrospray
ionization mass spectrometry. Because both the alpha-hydroxylated
fatty acid species (HFA) and the nonhydroxylated fatty acid
species (NFA) of these lipids occur in myelin, we have also
compared the HFA and NFA species. In addition to monomeric
Ca2+ complexes of all three lipids and oligomeric
Ca2+ complexes of both GalCer and GlcCer, Ca2+
also caused heterotypic complexation of CBS to both GalCer
and GlcCer. The heterotypic complexes had the greatest stability
of all oligomers formed and survived better at high declustering
potentials. Complexes of CBS with GlcCer were less stable
than those with GalCer. This was confirmed by using the
free sugars and glycosides making up the carbohydrate headgroups
of these lipids. HFA species of CBS and GalCer formed more
stable complexes than NFA species, but hydroxylation of
the fatty acid of GlcCer had no effect. The ability of GlcCer
to also complex with CBS, albeit with lower stability, may
allow GlcCer to partially compensate for the absence of
GalCer in the mouse mutant 6. FT-IR spectra indicated
that a strong interaction occurred between these glycolipids
even in the absence of Ca2+ 7. The
interaction caused the CBS micro-structures to be disrupted
so that CBS formed a single bilayer around the GalC multilayered
micro-structures, thus sequestering GalC from the external
aqueous phase. Thus the CBS and Galc interacted via trans
interaction across apposed bilayers which resulted in dehydration
of the head group and interface region of both lipid bilayers.
The strong interaction between these lipids may be involved
in stabilization of the myelin sheath 7.
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