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Binding, internalization and fate of H untingtin E xon1 fibrillar assemblies in mitotic and nonmitotic neuroblastoma cells
Author(s) -
RuizArlandis G.,
Pieri L.,
Bousset L.,
Melki R.
Publication year - 2016
Publication title -
neuropathology and applied neurobiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.538
H-Index - 95
eISSN - 1365-2990
pISSN - 0305-1846
DOI - 10.1111/nan.12258
Subject(s) - internalization , endocytic cycle , endocytosis , huntingtin , microbiology and biotechnology , cytosol , intracellular , mitosis , biology , fibril , cell , microtubule , chemistry , biochemistry , gene , mutant , enzyme
Aims The aggregation of H untingtin ( HTT ) protein and of its moiety encoded by its E xon1 ( HTTE xon1) into fibrillar structures inside neurons is the molecular hallmark of H untington's disease. Prion‐like transmission of these aggregates between cells has been demonstrated. The cell‐to‐cell transmission mechanisms of these protein aggregates and the susceptibility of different kinds of neuronal cells to these toxic assemblies still need assessment. Methods Here, we documented the binding to and internalization by differentiated and undifferentiated neuroblastoma cells of exogenous fibrillar HTTE xon1 and polyglutamine (poly Q ) polypeptides containing the same number of glutamines. We assessed the contribution of endocytosis to fibrillar HTTE xon1 uptake, their intracellular localization and fate. Results We observed that undifferentiated neuroblastoma cells were more susceptible to fibrillar HTTE xon1 and poly Q than their differentiated counterparts. Furthermore, we demonstrated that exogenous HTTE xon1 aggregates are mainly taken up by endocytosis and directed to lysosomal compartments in both mitotic and quiescent cells. Conclusions These data suggest that the rates of endocytic processes that differ in mitotic and quiescent cells strongly impact the uptake of exogenous HTTE xon1 and poly Q fibrils. This may be either the consequence of distinct metabolisms or distributions of specific protein partners for amyloid‐like assemblies at the surface of highly dividing versus quiescent cells. Our results highlight the importance of endocytic processes in the internalization of exogenous HTTE xon1 fibrils and suggest that a proportion of those assemblies reach the cytosol where they can amplify by recruiting the endogenous protein after escaping, by yet an unknown process, from the endo‐lysosomal compartments.