Gangliosides protection against lysosomal pathology of synucleinopathies

• Published in: Autophagy 2009-08, Vol.5 (6), p.860-861
• Main Authors: Wei, Jianshe, Fujita, Masayo, Sekigawa, Akio, Sekiyama, Kazunari, Waragai, Masaaki, Hashimoto, Makoto
• Format: Article
• Language: English
• Subjects: Autophagy - drug effects; Binding; Biology; Bioscience; Calcium; Cancer; Cell; Cell Line, Tumor; Cycle; Gangliosides - pharmacology; Humans; Intracellular Membranes - drug effects; Intracellular Membranes - metabolism; Landes; Lewy Body Disease - pathology; Lysosomes - drug effects; Lysosomes - pathology; Morpholines - pharmacology; Organogenesis; Parkinson Disease - pathology; Permeability - drug effects; Protective Agents - pharmacology; Proteins; Synucleins - metabolism
• ISSN: 1554-8627; 1554-8635
• DOI: 10.4161/auto.8825

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, Guillian-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 α-synuclein and mutant β-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.