期刊
JOURNAL OF NEUROCHEMISTRY
卷 118, 期 3, 页码 399-406出版社
WILEY-BLACKWELL
DOI: 10.1111/j.1471-4159.2011.07310.x
关键词
chemical chaperone; G(M1)-gangliosidosis; lysosome; neurodegeneration; Trk receptor
资金
- Ministry of Education, Culture, Science, Sports and Technology of Japan [13680918, 14207106, 18390299, 20790728, 21659257]
- Ministry of Health, Labour and Welfare of Japan [H17-Kokoro-019, H20-Kokoro-022]
- Japan Health Sciences Foundation
- Grants-in-Aid for Scientific Research [22390207, 18390299, 13680918, 14207106, 23591498, 21659257, 20790728] Funding Source: KAKEN
G(M1)-gangliosidosis is a fatal neurodegenerative disorder caused by deficiency of lysosomal acid beta-galactosidase (beta-gal). Accumulation of its substrate ganglioside G(M1) (G(M1)) in lysosomes and other parts of the cell leads to progressive neurodegeneration, but underlying mechanisms remain unclear. Previous studies demonstrated an essential role for interaction of G(M1) with tropomyosin receptor kinase (Trk) receptors in neuronal growth, survival and differentiation. In this study we demonstrate accumulation of G(M1) in the cell-surface rafts and lysosomes of the beta-gal knockout (beta-gal(-/-) mouse brain association with accumulation of Trk receptors and enhancement of its downstream signaling. Immunofluorescence and subcellular fractionation analysis revealed accumulation of Trk receptors in the late endosomes/lysosomes of the beta-gal(-/-) mouse brain and their association with ubiquitin and p62. Administration of a chemical chaperone to beta-gal(-/-) mouse expressing human mutant R201C protein resulted in a marked reduction of intracellular storage of G(M1) and phosphorylated Trk. These findings indicate that G(M1) accumulation in rafts causes activation of Trk signaling, which may participate in the pathogenesis of G(M1)-gangliosidosis.
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