A mechanistic study of proteasome inhibition-induced iron misregulation in dopamine neuron degeneration.
Neurosignals
; 20(4): 223-36, 2012.
Article
en En
| MEDLINE
| ID: mdl-22269801
ABSTRACT
Ubiquitin proteasome system (UPS) impairment and iron misregulation have been implicated in dopamine (DA) neuron degeneration in Parkinson's disease. As previously shown, proteasome inhibition in a rodent model can cause nigral neuron degeneration accompanied by iron accumulation. To investigate the involvement of iron in DA neuron degeneration, we generated an in vitro model by applying proteasome inhibitor lactacystin in DAergic cell line MES23.5 culture. We found that lactacystin caused marked increase in labile iron, reactive oxygen species and ubiquitin-conjugated protein aggregation prior to cell injury. These effects were attenuated by iron chelators or antioxidants. Furthermore, we demonstrated that the iron regulatory protein (IRP)/iron response element system contributed to UPS impairment-mediated DA neuron injury. We documented that IRP2 disruption resulted in an increase in transferrin receptor 1 (TfR1), a decrease in ferritin heavy chain (H-Frt), and eventually cell death. These findings provide insight into the mechanistic interplay between UPS impairment and iron misregulation and suggest that the disturbances in IRP2, TfR1 and H-Frt may contribute to DA neuron degeneration.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Contexto en salud:
6_ODS3_enfermedades_notrasmisibles
Problema de salud:
6_endocrine_disorders
Asunto principal:
Trastornos del Metabolismo del Hierro
/
Complejo de la Endopetidasa Proteasomal
/
Neuronas Dopaminérgicas
/
Degeneración Nerviosa
Límite:
Humans
Idioma:
En
Revista:
Neurosignals
Asunto de la revista:
NEUROLOGIA
Año:
2012
Tipo del documento:
Article
País de afiliación:
Estados Unidos