QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, August 22, 2007, 27(34):9009-9021; doi:10.1523/JNEUROSCI.2329-07.2007

This Article Full Text Full Text (PDF) Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (8) Citing Articles via Google Scholar Google Scholar Articles by Eckhardt, M. Articles by Gieselmann, V. Search for Related Content PubMed PubMed Citation Articles by Eckhardt, M. Articles by Gieselmann, V.

 Previous Article  |  Next Article 

Neurobiology of Disease
Sulfatide Storage in Neurons Causes Hyperexcitability and Axonal Degeneration in a Mouse Model of Metachromatic Leukodystrophy

Matthias Eckhardt,¹ Kerstin Khalaj Hedayati,⁴ Julika Pitsch,² Renate Lüllmann-Rauch,⁴ Heinz Beck,³ Simon Ngamli Fewou,¹ and Volkmar Gieselmann¹

¹Institute of Physiological Chemistry and ²Departments of Neuropathology and ³Epileptology, University of Bonn, 53115 Bonn, Germany, and ⁴Institute of Anatomy, University of Kiel, 24098 Kiel, Germany

Correspondence should be addressed to Dr. Matthias Eckhardt, Institut für Physiologische Chemie, Rheinische Friedrich-Wilhelms-Universität Bonn, Nussallee 11, 53115 Bonn, Germany. Email: eckhardt{at}institut.physiochem.uni-bonn.de

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.

Key words: arylsulfatase A; galactosyltransferase; galactosylceramide; lysosomal storage disorder; metachromatic leukodystrophy; sulfatide

---

Received Nov. 27, 2006; revised June 28, 2007; accepted June 29, 2007.

Correspondence should be addressed to Dr. Matthias Eckhardt, Institut für Physiologische Chemie, Rheinische Friedrich-Wilhelms-Universität Bonn, Nussallee 11, 53115 Bonn, Germany. Email: eckhardt{at}institut.physiochem.uni-bonn.de

This article has been cited by other articles:

				S.-B. Jeon, H. J. Yoon, S.-H. Park, I.-H. Kim, and E. J. Park Sulfatide, A Major Lipid Component of Myelin Sheath, Activates Inflammatory Responses As an Endogenous Stimulator in Brain-Resident Immune Cells J. Immunol., December 1, 2008; 181(11): 8077 - 8087. [Abstract] [Full Text] [PDF]

				Y. Sun, D. P. Witte, H. Ran, M. Zamzow, S. Barnes, H. Cheng, X. Han, M. T. Williams, M. R. Skelton, C. V. Vorhees, et al. Neurological deficits and glycosphingolipid accumulation in saposin B deficient mice Hum. Mol. Genet., August 1, 2008; 17(15): 2345 - 2356. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help