title: Gangliosides' protection against lysosomal pathology of synucleinopathies.
abstract: Gangliosides are abundantly expressed in the nervous system, and deregulated expression or activity of gangliosides is associated with the progression of various disorders, including lysosomal storage diseases, Guillain-Barre syndrome and Alzheimer disease. By contrast, previous studies show that GM1 ganglioside may act in a protective manner in the drug (e.g., MPTP and 6-OHDA)-induced Parkinsonian models, although the precise mechanisms have not been well addressed. In our recent publication, dementia with Lewy bodies (DLB)-linked neuroblastoma cells were treated with D-Threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP), an inhibitor of glycosyl ceramide synthetase. These PDMP-treated cells develop lysosomal diseases characterized by reduced lysosomal activity, enhanced lysosomal permeability and cytotoxicity. Furthermore, PDMP-mediated inhibition of autophagy-lysosomal pathway result in both accumulation of alpha-synuclein and mutant beta-synuclein. Finally, these phenotypes are reversed by ganglioside treatment. Taken together, our results suggest that endogenous gangliosides may play a protective role against the lysosomal pathology of synucleinopathies.
authors.affiliation: Laboratory for Chemistry and Metabolism, Tokyo Metropolitan Institute for Neuroscience, Fuchu, Tokyo, Japan.
authors.forename: Jianshe
authors.initials: J
authors.lastname: Wei
authors.forename: Masayo
authors.initials: M
authors.lastname: Fujita
authors.forename: Akio
authors.initials: A
authors.lastname: Sekigawa
authors.forename: Kazunari
authors.initials: K
authors.lastname: Sekiyama
authors.forename: Masaaki
authors.initials: M
authors.lastname: Waragai
authors.forename: Makoto
authors.initials: M
authors.lastname: Hashimoto
mesh_terms: D001343:Autophagy / Q000187:drug effects; D045744:Cell Line, Tumor; D005732:Gangliosides / Q000494:pharmacology*; D006801:Humans; D007425:Intracellular Membranes / Q000187:drug effects / Q000378:metabolism; D020961:Lewy Body Disease / Q000473:pathology; D008247:Lysosomes / Q000187:drug effects* / Q000473:pathology*; D009025:Morpholines / Q000494:pharmacology; D010300:Parkinson Disease / Q000473:pathology; D010539:Permeability / Q000187:drug effects; D020011:Protective Agents / Q000494:pharmacology*; D051843:Synucleins / Q000378:metabolism*
chemical_list: D005732:Gangliosides; D009025:Morpholines; D020011:Protective Agents; D051843:Synucleins; C033110:RV 538