期刊
FREE RADICAL BIOLOGY AND MEDICINE
卷 72, 期 -, 页码 176-190出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2014.04.012
关键词
Hsp27; Cu2+ binding; Amyloid fibril; alpha-Synuclein; Reactive oxygen species; Free radicals
资金
- Senior Research Fellowship from the Council of Scientific and Industrial Research, New Delhi
- Department of Science and Technology, New Delhi
- BioAge Project Grant - Council of Scientific and Industrial Research, New Delhi, India [BSC208]
Aberrant copper homeostasis and oxidative stress have critical roles in several neurodegenerative diseases. Expression of heat-shock protein 27 (Hsp27) is elevated under oxidative stress as well as upon treatment with Cu2+, and elevated levels of Hsp27 are found in the brains of patients with Alzheimer and Parkinson diseases. We demonstrate, using steady-state and time-resolved fluorescence spectroscopy as well as isothermal titration calorimetry studies, that Hsp27 binds Cu2+ with high affinity (K-d similar to 10(-11) M). Treating IMR-32 human neuroblastoma cells with Cu2+ leads to upregulation of endogenous Hsp27. Further, overexpression of Hsp27 in IMR-32 human neuroblastoma cells confers cytoprotection against Cu2+-induced cell death. Hsp27 prevents the deleterious interaction of Cu2+ with alpha-synuclein, the protein involved in Parkinson disease and synucleinopathies. Hsp27 attenuates Cu2+- or Cu2+-alpha-synuclein-mediated generation of reactive oxygen species and confers cytoprotection on IMR-32 cells as well as on mouse primary neural precursor cells. Hsp27 prevents Cu2+-ascorbate or Cu2+-alpha-synuclein-ascorbate treatment-induced increase in mitochondrial superoxide level and mitochondrial disorganization in IMR-32 cells. Hsp27 dislodges the alpha-synuclein-bound Cu2+ and prevents the Cu2+-mediated amyloidogenesis of a-synuclein. Our findings that Hsp27 binds Cu2+ with high affinity leading to beneficial effects and that Hsp27 can dislodge Cu2+ from a-synuclein, preventing amyloid fibril formation, indicate potential therapeutic strategies for neurodegenerative diseases involving aberrant Cu2+ homeostasis. (C) 2014 Elsevier Inc. All rights reserved.
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