Altered lysosomal positioning affects lysosomal functions in a cellular model of Huntington's disease
| Autor: | Michael L. Lu, Matthew Sacino, Jianning Wei, Christine Erie, Lauren Houle |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
Huntingtin
Nerve Tissue Proteins mTORC1 Mechanistic Target of Rapamycin Complex 1 Biology Article Pathogenesis Mice Huntington's disease Autophagy medicine Huntingtin Protein Animals Gene Knock-In Techniques Cells Cultured LAMP1 TOR Serine-Threonine Kinases General Neuroscience Biological Transport Fibroblasts medicine.disease Corpus Striatum Cell biology Disease Models Animal Huntington Disease Multiprotein Complexes Cellular model Lysosomes |
| Zdroj: | European Journal of Neuroscience. 42:1941-1951 |
| ISSN: | 0953-816X |
| Popis: | 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 (mTORC1). 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 mTORC1 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. |
| Databáze: | OpenAIRE |
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