title: Lysosomal accumulation of Trk protein in brain of GM₁ -gangliosidosis mouse and its restoration by chemical chaperone.
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.
authors.affiliation: Division of Functional Genomics, Research Center for Bioscience and Technology, Nishi-cho, Yonago, Japan.
authors.forename: Ayumi
authors.initials: A
authors.lastname: Takamura
authors.forename: Katsumi
authors.initials: K
authors.lastname: Higaki
authors.forename: Haruaki
authors.initials: H
authors.lastname: Ninomiya
authors.forename: Tomoko
authors.initials: T
authors.lastname: Takai
authors.forename: Junichiro
authors.initials: J
authors.lastname: Matsuda
authors.forename: Masami
authors.initials: M
authors.lastname: Iida
authors.forename: Kousaku
authors.initials: K
authors.lastname: Ohno
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Eiji
authors.initials: E
authors.lastname: Nanba
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D001921:Brain / Q000473:pathology; D001923:Brain Chemistry / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D005455:Fluorescent Antibody Technique; D016537:Gangliosidosis, GM1 / Q000378:metabolism*; D006595:Hexosamines / Q000494:pharmacology*; D006801:Humans; D047468:Immunoprecipitation; D008247:Lysosomes / Q000378:metabolism*; D021962:Membrane Microdomains / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018832:Molecular Chaperones / Q000494:pharmacology*; D009414:Nerve Growth Factors / Q000502:physiology; D010766:Phosphorylation; D020917:Receptor, trkA / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D001616:beta-Galactosidase / Q000235:genetics / Q000494:pharmacology
chemical_list: D006595:Hexosamines; D018832:Molecular Chaperones; C116532:N-octyl-beta-valienamine; D009414:Nerve Growth Factors; D020917:Receptor, trkA; D001616:beta-Galactosidase