Lysosomal accumulation of Trk protein in brain of GM1‐gangliosidosis mouse and its restoration by chemical chaperone

J. Neurochem. (2011) 118, 399–406. Abstract GM1-gangliosidosis is a fatal neurodegenerative disorder caused by deficiency of lysosomal acid β-galactosidase (β-gal). Accumulation of its substrate ganglioside GM1 (GM1) 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 GM1 with tropomyosin receptor kinase (Trk) receptors in neuronal growth, survival and differentiation. In this study we demonstrate accumulation of GM1 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 GM1 and phosphorylated Trk. These findings indicate that GM1 accumulation in rafts causes activation of Trk signaling, which may participate in the pathogenesis of GM1-gangliosidosis.