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

Abstract

Sandhoff disease (SD) is a lysosomal storage disorder due to mutations in the gene encoding for the beta-subunit of beta-hexosaminidase, that result in beta-hexosaminidase A (alphabeta) and beta-hexosaminidase B (betabeta) 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.

Ganglioside accumulation in activated glia in the developing brain: comparison between WT and GalNAcT KO mice

“…Even when a primary defi ciency in a lysosomal glycohydrolase, activator protein, or saposin directly involved in the degradation of GM2 or GM3 ( 52 ) is not present, the accumulation of GM2/GM3 appears to occur, at least in part, in the endosomal/lysosomal system ( 26,29,30,34,53 ) and/or in lipid rafts ( 24,27,33 ). As well as for defi ciencies in catabolic proteins not directly involved in degradation of these gangliosides, defects in traffi cking of gangliosides from endosomes to the Golgi apparatus ( 53,54 ) or from late endosomes to lysosomes ( 55,56 ) also observed in some lysosomal storage diseases can produce similar accumulation. In chronic diseases, such ganglioside accumulation is typically detected in neurons ( 29,30,34,57 ) and, in some cases, in activated microglia ( 51 ).…”

Elevation of GM2 ganglioside during ethanol‐induced apoptotic neurodegeneration in the developing mouse brain

“…In lysosomal storage diseases such as Sandhoff disease and Niemann‐Pick disease, it has been indicated that accumulated GM2 in neurons are localized mainly in lysosomes/late endosomes because of defective lysosomal degradation and/or defective trafficking of gangliosides from endosomes to the Golgi apparatus (Marks and Pagano 2002; Vitner et al. 2010) or from late endosomes to lysosomes (Tancini et al. 2009; Lloyd‐Evans and Platt 2010).…”

“…In lysosomal storage diseases such as Sandhoff disease and Niemann-Pick disease, it has been indicated that accumulated GM2 in neurons are localized mainly in lysosomes/late endosomes because of defective lysosomal degradation and/ or defective trafficking of gangliosides from endosomes to the Golgi apparatus (Marks and Pagano 2002;Vitner et al 2010) or from late endosomes to lysosomes (Tancini et al 2009;Lloyd-Evans and Platt 2010). Ethanol has been shown to induce perturbation in endocytic processes of sphingolipids (Ravasi et al 2002;Tomás et al 2004), which may be related to the observed GM2 accumulation in a late endosome/lysosome/phagolysosome fraction of the brain.…”

Oncogenic H-Ras Up-Regulates Acid β-Hexosaminidase by a Mechanism Dependent on the Autophagy Regulator TFEB

“…Recently, it was shown that the activation of TFEB, a transcription factor that controls lysosomal biogenesis and function, is accompanied by an increase of mature β-hexosaminidase on cell surface [21]. From a pathological point of view, mutations in the α- and β-subunit coding genes lead to the development of Tay-Sachs and Sandhoff diseases, respectively, which are severe lysosomal storage disorders associated with neurodegeneration [22]. In addition, β-hexosaminidase altered expression has been often associated with cancer [23], [24] and namely the presence of Hex S has been observed in leukaemic cells but not in their normal counterparts [25].…”