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Altered lysosomal positioning affects lysosomal functions in a cellular model of Huntington's disease
Author(s) -
Erie Christine,
Sacino Matthew,
Houle Lauren,
Lu Michael L.,
Wei Jianning
Publication year - 2015
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1111/ejn.12957
Subject(s) - huntingtin , huntington's disease , microbiology and biotechnology , lysosome , autophagy , huntingtin protein , biology , organelle , mtorc1 , pathogenesis , mutation , mutant , biochemistry , disease , gene , signal transduction , immunology , medicine , apoptosis , pi3k/akt/mtor pathway , enzyme
Huntington's disease ( HD ) is a hereditary and devastating neurodegenerative disorder caused by a mutation in the huntingtin protein. Understanding the functions of normal and mutant huntingtin protein is the key to revealing the pathogenesis of HD and developing therapeutic targets. Huntingtin plays an important role in vesicular and organelle trafficking. Lysosomes are dynamic organelles that integrate several degradative pathways and regulate the activity of mammalian target of rapamycin complex 1 ( mTORC 1). In the present study, we found that the perinuclear accumulation of lysosomes was increased in a cellular model of HD derived from HD knock‐in mice and primary fibroblasts from an HD patient. This perinuclear lysosomal accumulation could be reversed when normal huntingtin was overexpressed in HD cells. When we further investigated the functional significance of the increased perinuclear lysosomal accumulation in HD cells, we demonstrated that basal mTORC 1 activity was increased in HD cells. In addition, autophagic influx was also increased in HD cells in response to serum deprivation, which leads to premature fusion of lysosomes with autophagosomes. Taken together, our data suggest that the increased perinuclear accumulation of lysosomes may play an important role in HD pathogenesis by altering lysosomal‐dependent functions.