Altered lysosomal positioning affects lysosomal functions in a cellular model of Huntington's disease.
Eur J Neurosci
; 42(3): 1941-51, 2015 Aug.
Article
en En
| MEDLINE
| ID: mdl-25997742
ABSTRACT
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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Enfermedad de Huntington
/
Fibroblastos
/
Lisosomas
/
Proteínas del Tejido Nervioso
Límite:
Animals
Idioma:
En
Revista:
Eur J Neurosci
Asunto de la revista:
NEUROLOGIA
Año:
2015
Tipo del documento:
Article
País de afiliación:
Estados Unidos