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Occurrence of an anomalous endocytic compartment in fibroblasts from Sandhoff disease patients

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Abstract

Sandhoff disease (SD) is a lysosomal storage disorder due to mutations in the gene encoding for the β-subunit of β-hexosaminidase, that result in β-hexosaminidase A (αβ) and β-hexosaminidase B (ββ) deficiency. This leads to the storage of GM2 ganglioside in endosomes and lysosomes, which ends in a progressive neurodegeneration. Currently, very little is known about the biochemical pathways leading from GM2 ganglioside accumulation to pathogenesis. Defects in transport and sorting by the endosomal–lysosomal system have been described for several lysosomal storage disorders. Here, we have investigated the endosomal–lysosomal compartment in fibroblasts from SD patients and observed that both late endosomes and lysosomes, but not early endosomes, have a higher density in comparison with normal fibroblasts. Moreover, Sandhoff fibroblasts have an intracellular distribution of terminal endocytic organelles that differs from the characteristic perinuclear punctate pattern observed in normal fibroblasts and endocytic vesicles also appear larger. These findings reveal the occurrence of an alteration in the terminal endocytic organelles of Sandhoff fibroblasts, suggesting an involvement of this compartment in the disruption of cell metabolic and signalling pathways and in the onset of the pathological state.

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Acknowledgments

This work was supported by COFIN-PRIN (Cofinanziamento-Progetto di Ricerca di Interesse Nazionale) and FIRB (Fondo per gli Investimenti della Ricerca di Base) grants to C.E. This work was also supported by Fondazione Cassa di Risparmio di Perugia, Grant 2008.021.375 to C.E. We thank the “Diagnosi PrePostnatale Malattie Metaboliche” Laboratory (G.Gaslini Institute) for providing us with specimens from the “Cell line and DNA bank from patients affected by Genetic diseases” Biobank- Telethon Genetic Biobank Network (project no. GTB07001A). We thank Dr. Maria Ragano Caracciolo for the valuable comments and critical reading of the manuscript.

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Authors and Affiliations

  1. Department of Experimental Medicine and Biochemical Sciences, University of Perugia, via del Giochetto, 06126, Perugia, Italy

    Brunella Tancini, Alessandro Magini, Lorena Urbanelli, Virginia Ciccarone & Carla Emiliani

  2. Department of Chemistry, University of Perugia, via Elce di Sotto, 06125, Perugia, Italy

    Loredana Latterini & Fausto Elisei

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  1. Brunella Tancini
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  2. Alessandro Magini
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  3. Loredana Latterini
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  4. Lorena Urbanelli
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  5. Virginia Ciccarone
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  6. Fausto Elisei
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  7. Carla Emiliani
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Correspondence to Carla Emiliani.

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Tancini, B., Magini, A., Latterini, L. et al. Occurrence of an anomalous endocytic compartment in fibroblasts from Sandhoff disease patients. Mol Cell Biochem 335, 273–282 (2010). https://doi.org/10.1007/s11010-009-0277-0

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  • DOI: https://doi.org/10.1007/s11010-009-0277-0

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