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Lysosomal accumulation of Trk protein in brain of G M1 ‐gangliosidosis mouse and its restoration by chemical chaperone
Author(s) -
Takamura Ayumi,
Higaki Katsumi,
Ninomiya Haruaki,
Takai Tomoko,
Matsuda Junichiro,
Iida Masami,
Ohno Kousaku,
Suzuki Yoshiyuki,
Nanba Eiji
Publication year - 2011
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2011.07310.x
Subject(s) - trk receptor , endosome , microbiology and biotechnology , neurodegeneration , biology , receptor , intracellular , neurotrophin , biochemistry , medicine , disease
J. Neurochem. (2011) 118 , 399–406. Abstract G M1 ‐gangliosidosis is a fatal neurodegenerative disorder caused by deficiency of lysosomal acid β‐galactosidase (β‐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 β‐gal knockout (β‐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 β‐gal−/− mouse brain and their association with ubiquitin and p62. Administration of a chemical chaperone to β‐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.