6-Hydroxydopamine disrupts cellular copper homeostasis in human neuroblastoma SH-SY5Y cells
| Autor: | Mao Kondo, Fuka Kamijo, Hirokazu Hara, Tetsuo Adachi, Tetsuro Kamiya |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
SH-SY5Y ATP7A Biophysics Substantia nigra Protein degradation Biochemistry Biomaterials ATOX1 03 medical and health sciences Neuroblastoma Adrenergic Agents Copper Transport Proteins Tumor Cells Cultured Homeostasis Humans Oxidopamine Hydroxydopamine 030102 biochemistry & molecular biology Cell Death Chemistry Dopaminergic Metals and Alloys Cell biology Oxidative Stress 030104 developmental biology nervous system Chemistry (miscellaneous) Copper-Transporting ATPases Reactive Oxygen Species Intracellular Copper Molecular Chaperones |
| Zdroj: | Metallomics : integrated biometal science. 13(7) |
| ISSN: | 1756-591X |
| Popis: | Copper (Cu) is an essential trace element that plays an important role in maintaining neuronal functions such as the biosynthesis of neurotransmitters. In contrast, exposure to excess Cu results in cell injury. Therefore, intracellular Cu levels are strictly regulated by proteins related to Cu-trafficking, including ATP7A. Parkinson's disease (PD) is a neurodegenerative disorder and is characterized by the loss of dopaminergic neurons in the substantia nigra. Recently, the abnormality of Cu homeostasis was demonstrated to be related to the pathogenesis of PD. However, the association between Cu dyshomeostasis and PD remains unclear. In this study, we examined the effects of 6-hydroxydopamine (6-OHDA), a neurotoxin used for the production of PD model animals, on cellular Cu trafficking in human neuroblastoma SH-SY5Y cells. 6-OHDA reduced the protein levels of the Cu exporter ATP7A and the Cu chaperone Atox1, but not CTR1, a Cu importer; however, it did not affect the expression of ATP7A and Atox1 mRNAs. The decreased levels of ATP7A and Atox1 proteins were restored by the antioxidant N-acetylcysteine and the lysosomal inhibitor bafilomycin A1. This suggests that 6-OHDA-induced oxidative stress facilitates the degradation of these proteins. In addition, the amount of intracellular Cu after exposure to CuCl2 was significantly higher in cells pretreated with 6-OHDA than in untreated cells. Moreover, 6-OHDA reduced the protein levels of the cuproenzyme dopamine β-hydroxylase that converts dopamine to noradrenaline. Thus, this study suggests that 6-OHDA disrupts Cu homeostasis through the dysregulation of cellular Cu trafficking, resulting in the dysfunction of neuronal cells. |
| Databáze: | OpenAIRE |
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