Neuromelanin induces oxidative stress in mitochondria through release of iron: mechanism behind the inhibition of 26S proteasome.

Abstract	Parkinson's disease is characterized by the selective depletion of dopamine neurons in the substantia nigra, particular those containing neuromelanin. Involvement of neuromelanin in the pathogenesis may be either cytotoxic or protective. Recently we found that neuromelanin reduces the activity of 26S proteasome. In this paper, the detailed mechanisms behind the reduced activity were studied using neuromelanin isolated from the human brain. Neuromelanin increased the oxidative stress, but synthetic melanin did not. Superoxide dismutase and deferoxamine completely suppressed the increase, indicating that superoxide produced by an iron-mediated reaction plays a central role. Iron was shown to reduce in situ 26S proteasome activity in SH-SY5Y cells and the reduction was protected by antioxidants. These results suggest that iron released from neuromelanin increases oxidative stress in mitochondria, and then causes mitochondrial dysfunction and reduces proteasome function. The role of neuromelanin is discussed in relation to the selective vulnerability of dopamine neurons in Parkinson's disease.
Authors	M Shamoto-Nagai, W Maruyama, H Yi, Y Akao, F Tribl, M Gerlach, T Osawa, P Riederer, M Naoi
Journal	Journal of neural transmission (Vienna, Austria : 1996) (J Neural Transm (Vienna)) Vol. 113 Issue 5 Pg. 633-44 (May 2006) ISSN: 0300-9564 [Print] Austria
PMID	16362626 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Antioxidants Melanins Reactive Oxygen Species Siderophores neuromelanin Nitric Oxide Acrolein Iron Proteasome Endopeptidase Complex ATP dependent 26S protease Deferoxamine
Topics	Acrolein (pharmacology) Analysis of Variance Antioxidants (pharmacology) Blotting, Western (methods) Brain (metabolism) Cell Line, Tumor Deferoxamine (pharmacology) Dose-Response Relationship, Drug Drug Interactions Humans Iron (metabolism) Melanins (pharmacology) Mitochondria (drug effects) Neuroblastoma Nitric Oxide (metabolism) Oxidative Stress (drug effects) Proteasome Endopeptidase Complex (physiology) Reactive Oxygen Species (metabolism) Siderophores (pharmacology) Spectrometry, Fluorescence (methods) Transfection

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.

Realize the full power of the drug-disease research graph!