Persistence of psychosine in brain lipid rafts is a limiting factor in the therapeutic recovery of a mouse model for Krabbe disease.
Sphingolipids are intrinsic components of membrane lipid rafts. The abnormal accumulation of these molecules may introduce architectural and functional changes in these domains, leading to cellular dysfunction. Galactosylsphingosine (psychosine) is a pathogenic lipid raft-associated molecule whose accumulation leads to brain deterioration and irreversible neurological handicap in the incurable leukodystrophy Krabbe disease (KD). The relevance of clearing excessive levels of pathogenic psychosine from lipid rafts in therapy for KD has not been investigated. The work presented here demonstrates that psychosine inhibits raft-mediated endocytosis in neural cells. In addition, although in vitro enzyme reconstitution is sufficient for the reversal of related endocytic defects in affected neural cells, traditional in vivo enzyme therapies in the mouse model of KD appear to be insufficient for complete removal of pathogenic levels of raft-associated psychosine. This work describes a mechanism that may contribute to limiting the in vivo efficacy of traditional therapies for KD.
Department of Anatomy and Cell Biology, University of Illinois, Chicago, Illinois, USA.
A B
AB
White
F
F
Galbiati
M I
MI
Givogri
A
A
Lopez Rosas
X
X
Qiu
R
R
van Breemen
E R
ER
Bongarzone
D000818:Animals; D000831:Animals, Newborn; D016026:Bone Marrow Transplantation / Q000379:methods; D001921:Brain / Q000473:pathology; D002478:Cells, Cultured; D002772:Cholera Toxin / Q000378:metabolism; D002966:Clathrin; D004195:Disease Models, Animal; D004705:Endocytosis / Q000235:genetics / Q000502:physiology; D056947:Enzyme Replacement Therapy / Q000379:methods; D005698:Galactosylceramidase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007965:Leukodystrophy, Globoid Cell / Q000473:pathology* / Q000628:therapy*; D013058:Mass Spectrometry; D021962:Membrane Microdomains / Q000187:drug effects*; D051379:Mice; D009474:Neurons / Q000473:pathology*; D011493:Protein Kinase C / Q000378:metabolism; D011609:Psychosine / Q000378:metabolism / Q000494:pharmacology*; D013997:Time Factors
D002966:Clathrin; D011609:Psychosine; D002772:Cholera Toxin; D011493:Protein Kinase C; D005698:Galactosylceramidase
Dev Neurosci. 2006;28(1-2):81-91
16508306
Science. 1987 Feb 6;235(4789):670-4
3101176
J Biol Chem. 2005 Jul 8;280(27):25892-900
15886206
J Lipid Res. 2006 Jul;47(7):1478-92
16645197
Proc Natl Acad Sci U S A. 2010 Mar 2;107(9):4141-6
20160074
Cell. 2004 Sep 3;118(5):591-605
15339664
Am J Physiol Cell Physiol. 2009 Oct;297(4):C835-44
19605734
Phys Rev E Stat Nonlin Soft Matter Phys. 2008 Aug;78(2 Pt 1):021908
18850866
J Neurosci Res. 2009 Jun;87(8):1748-59
19185028
N Engl J Med. 1998 Apr 16;338(16):1119-26
9545360
J Neurochem. 1996 Mar;66(3):1118-24
8769874
Nature. 1997 Jun 5;387(6633):569-72
9177342
Science. 1984 May 18;224(4650):753-5
6719111
Science. 1988 Feb 26;239(4843):1035-8
3278379
Brain. 1980 Sep;103(3):695-710
7417782
Biochim Biophys Acta. 1986 Nov 6;862(1):199-204
3768363
Bone Marrow Transplant. 2008 May;41(9):831-2
18246117
J Inherit Metab Dis. 1993;16(4):733-43
7692130
Science. 1984 Sep 7;225(4666):1052-4
6382609
Nature. 1983 Oct 20-26;305(5936):713-5
6633639
J Neurosci. 2007 Dec 12;27(50):13730-8
18077684
Biochem Mol Med. 1996 Aug;58(2):142-50
8812733
J Biol Chem. 2004 May 7;279(19):20392-400
15007081
Pediatr Res. 2002 Jan;51(1):40-7
11756638
J Neurochem. 2008 Feb;104(4):1055-64
17986221
J Biol Chem. 2006 Aug 18;281(33):23326-40
16740633
J Biol Chem. 2004 Oct 22;279(43):44945-54
15322084
Cell Physiol Biochem. 2009;24(5-6):627-34
19910703
N Engl J Med. 2005 May 19;352(20):2069-81
15901860
J Neurochem. 2003 Sep;86(6):1428-40
12950451
Dev Neurosci. 2008;30(5):340-57
18667806
J Child Neurol. 2003 Sep;18(9):595-603
14572137
J Cell Biol. 2007 Mar 26;176(7):895-901
17371832
J Neurosci. 2009 May 13;29(19):6068-77
19439584
J Neurosci. 2006 Mar 22;26(12):3109-19
16554462
J Lipid Res. 2001 Dec;42(12):2092-5
11734583
J Gene Med. 2006 Aug;8(8):962-71
16732552
J Biol Chem. 2004 Nov 12;279(46):48055-62
15345719
J Neurosci. 2002 Jan 15;22(2):437-45
11784788
Proc Natl Acad Sci U S A. 1982 Jan;79(2):451-5
6952195
Clin Chim Acta. 1992 Jan 31;205(1-2):87-96
1521344
Proc Natl Acad Sci U S A. 2007 Jun 5;104(23):9638-43
17535898