title: Sulfatide storage in neurons causes hyperexcitability and axonal degeneration in a mouse model of metachromatic leukodystrophy.
abstract: Metachromatic leukodystrophy is a lysosomal storage disorder caused by deficiency in the sulfolipid degrading enzyme arylsulfatase A (ASA). In the absence of a functional ASA gene, 3-O-sulfogalactosylceramide (sulfatide; SGalCer) and other sulfolipids accumulate. The storage is associated with progressive demyelination and various finally lethal neurological symptoms. Lipid storage, however, is not restricted to myelin-producing cells but also occurs in neurons. It is unclear whether neuronal storage contributes to symptoms of the patients. Therefore, we have generated transgenic ASA-deficient [ASA(-/-)] mice overexpressing the sulfatide synthesizing enzymes UDP-galactose:ceramide galactosyltransferase (CGT) and cerebroside sulfotransferase (CST) in neurons to provoke neuronal lipid storage. CGT-transgenic ASA(-/-) [CGT/ASA(-/-)] mice showed an accumulation of C18:0 fatty acid-containing SGalCer in the brain. Histochemically, an increase in sulfolipid storage could be detected in central and peripheral neurons of both CGT/ASA(-/-) and CST/ASA(-/-) mice compared with ASA(-/-) mice. CGT/ASA(-/-) mice developed severe neuromotor coordination deficits and weakness of hindlimbs and forelimbs. Light and electron microscopic analyses demonstrated nerve fiber degeneration in the spinal cord of CGT/ASA(-/-) mice. CGT/ASA(-/-) and, to a lesser extent, young ASA(-/-) mice exhibited cortical hyperexcitability, with recurrent spontaneous cortical EEG discharges lasting 5-15 s. These observations suggest that SGalCer accumulation in neurons contributes to disease phenotype.
authors: Institute of Physiological Chemistry, University of Bonn, 53115 Bonn, Germany. eckhardt@institut.physiochem.uni-bonn.de
authors: Matthias
authors: M
authors: Eckhardt
authors: Kerstin Khalaj
authors: KK
authors: Hedayati
authors: Julika
authors: J
authors: Pitsch
authors: Renate
authors: R
authors: Lüllmann-Rauch
authors: Heinz
authors: H
authors: Beck
authors: Simon Ngamli
authors: SN
authors: Fewou
authors: Volkmar
authors: V
authors: Gieselmann
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal; D002540:Cerebral Cortex / Q000473:pathology / Q000503:physiopathology*; D002553:Cerebroside-Sulfatase / Q000172:deficiency / Q000378:metabolism*; D004195:Disease Models, Animal; D004569:Electroencephalography / Q000379:methods; D017403:In Situ Hybridization / Q000379:methods; D007966:Leukodystrophy, Metachromatic / Q000150:complications / Q000378:metabolism / Q000473:pathology; D008055:Lipids / Q000032:analysis; D051379:Mice; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D009048:Motor Skills / Q000502:physiology; D051146:N-Acylsphingosine Galactosyltransferase / Q000172:deficiency; D009410:Nerve Degeneration / Q000209:etiology* / Q000235:genetics; D009474:Neurons / Q000201:enzymology* / Q000648:ultrastructure; D051381:Rats; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013116:Spinal Cord / Q000473:pathology; D013433:Sulfoglycosphingolipids / Q000378:metabolism*; D015238:Sulfotransferases / Q000235:genetics
chemical_list: D008055:Lipids; D013433:Sulfoglycosphingolipids; D051146:N-Acylsphingosine Galactosyltransferase; D015238:Sulfotransferases; C020556:galactosylceramide sulfotransferase; D002553:Cerebroside-Sulfatase
references: J Neuropathol Exp Neurol. 1999 Jun;58(6):644-53
references: 10374755
references: Neurosci Lett. 1999 Oct 1;273(2):93-6
references: 10505624
references: Brain Res. 1999 Nov 20;847(2):352-6
references: 10575108
references: J Neurocytol. 1999 Apr-May;28(4-5):383-95
references: 10739578
references: J Neurosci. 2000 Aug 15;20(16):6021-9
references: 10934251
references: Brain Res. 2001 Jul 13;907(1-2):35-43
references: 11430883
references: Acta Neuropathol. 2001 May;101(5):491-8
references: 11484821
references: Virchows Arch. 2001 Jul;439(1):90-6
references: 11499846
references: Histochem Cell Biol. 2001 Aug;116(2):161-9
references: 11685544
references: J Biol Chem. 2002 Jun 7;277(23):20386-98
references: 11919180
references: J Neurosci Res. 2002 Jul 1;69(1):86-93
references: 12111819
references: Diabetes. 2002 Aug;51(8):2514-21
references: 12145165
references: Biochem J. 2002 Nov 15;368(Pt 1):317-24
references: 12175333
references: Acta Neuropathol. 2004 Oct;108(4):261-71
references: 15322834
references: J Neurocytol. 2004 Jul;33(4):417-27
references: 15520527
references: J Membr Biol. 2004 Sep 15;201(2):77-84
references: 15630545
references: Eur J Neurosci. 2005 Feb;21(3):711-20
references: 15733089
references: Glia. 2005 Nov 15;52(3):190-8
references: 15968630
references: J Neurochem. 2005 Jul;94(2):469-81
references: 15998297
references: FEBS J. 2006 Apr;273(8):1782-90
references: 16623713
references: Br J Pharmacol. 2006 Dec;149(8):1031-8
references: 17075570
references: Anal Biochem. 1985 Oct;150(1):111-6
references: 4083472
references: J Biol Chem. 1972 Feb 25;247(4):1055-6
references: 5010062
references: Biochemistry. 1979 Nov 27;18(24):5294-9
references: 518835
references: Neurology. 1968 Nov;18(11):1140-2
references: 5751920
references: Biochemistry. 1969 Feb;8(2):506-12
references: 5793706
references: J Neurochem. 1982 Jan;38(1):233-41
references: 6955451
references: Int J Dev Neurosci. 1995 Nov;13(7):715-22
references: 8787862
references: Proc Natl Acad Sci U S A. 1996 Dec 10;93(25):14821-6
references: 8962139
references: Clin Genet. 1996 Nov;50(5):287-92
references: 9007312
references: Am J Med Genet. 1997 Mar 31;69(3):335-40
references: 9096767
references: J Neurosci. 1997 Jun 15;17(12):4688-99
references: 9169529
references: J Inherit Metab Dis. 1998 Aug;21(5):564-74
references: 9728336