help button home button Am J Pathol Epitomics, Inc.
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Originally published online as doi:10.2353/ajpath.2009.080680 on April 6, 2009

Published online before print April 6, 2009
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
ajpath.2009.080680v1
174/5/1891    most recent
Right arrow Purchase Article
Right arrow View Shopping Cart
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Wei, J.
Right arrow Articles by Hashimoto, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Wei, J.
Right arrow Articles by Hashimoto, M.
Related Collections
Right arrowRelated Article
(American Journal of Pathology. 2009;174:1891-1909.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.080680

Protective Role of Endogenous Gangliosides for Lysosomal Pathology in a Cellular Model of Synucleinopathies

Jianshe Wei*, Masayo Fujita*, Masaaki Nakai*, Masaaki Waragai*, Akio Sekigawa*, Shuei Sugama*, Takato Takenouchi*{dagger}, Eliezer Masliah{ddagger} and Makoto Hashimoto*

From the Laboratory for Chemistry and Metabolism,* Tokyo Metropolitan Institute for Neuroscience, Tokyo, Japan; the Transgenic Animal Research Center,{dagger} National Institute of Agrobiological Sciences, Ibaraki, Japan; and the Department of Neurosciences,{ddagger} University of California, San Diego, La Jolla, California

Gangliosides may be involved in the pathogenesis of Parkinson’s disease and related disorders, although the precise mechanisms governing this involvement remain unknown. In this study, we determined whether changes in endogenous ganglioside levels affect lysosomal pathology in a cellular model of synucleinopathy. For this purpose, dementia with Lewy body-linked P123H β-synuclein (β-syn) neuroblastoma cells transfected with {alpha}-synuclein were used as a model system because these cells were characterized as having extensive formation of lysosomal inclusions bodies. Treatment of these cells with D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP), an inhibitor of glycosyl ceramide synthase, resulted in various features of lysosomal pathology, including compromised lysosomal activity, enhanced lysosomal membrane permeabilization, and increased cytotoxicity. Consistent with these findings, expression levels of lysosomal membrane proteins, ATP13A2 and LAMP-2, were significantly decreased, and electron microscopy demonstrated alterations in the lysosomal membrane structures. Furthermore, the accumulation of both P123H β-syn and {alpha}-synuclein proteins was significant in PDMP-treated cells because of the suppressive effect of PDMP on the autophagy pathway. Finally, the detrimental effects of PDMP on lysosomal pathology were significantly ameliorated by the addition of gangliosides to the cultured cells. These data suggest that endogenous gangliosides may play protective roles against the lysosomal pathology of synucleinopathies.


Related Article

This Month in AJP
Am. J. Pathol. 2009 174: 1573-1574. [Abstract] [Full Text] [PDF]





HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Copyright © 2009 by the American Society for Investigative Pathology.