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Neurodegenerative diseases and oxidative stress

Nature Reviews Drug Discovery volume 3, pages 205214 (2004) | Download Citation

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Abstract

Oxidative stress has been implicated in the progression of Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. Oxygen is vital for life but is also potentially dangerous, and a complex system of checks and balances exists for utilizing this essential element. Oxidative stress is the result of an imbalance in pro-oxidant/antioxidant homeostasis that leads to the generation of toxic reactive oxygen species. The systems in place to cope with the biochemistry of oxygen are complex, and many questions about the mechanisms of oxygen regulation remain unanswered. However, this same complexity provides a number of therapeutic targets, and different strategies, including novel metal–protein attenuating compounds, aimed at a variety of targets have shown promise in clinical studies.

Key points

  • Oxidative stress has been implicated in the progression of a number of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis(ALS).

  • These diseases are characterized by extensive oxidative damage to lipids, proteins and DNA. This damage can lead to cell death by a variety of different mechanisms, either by deactivating important processes or by upregulating toxic cascades.

  • Oxidative stress is the result of an imbalance in the pro-oxidant/antioxidant homeostasis leading to the generation of toxic reactive oxygen species (ROS). ROS have a normal metabolic role in cell signalling and are generated by the interaction of oxygen with redox-active metal ions. As ROS can be damaging both metals and ROS are tightly regulated.

  • Genetics has identified Aβ, α-synuclein and SOD as playing a pivotal role in AD, PD and ALS, respectively. These proteins are the major components of the deposits associated with these diseases. All these proteins have been shown to interact with redox-active metal ions with the subsequent generation of ROS.

  • Aβ will coordinate copper and iron and generate H2O2 with the further generation of ROS through Fenton chemistry. α-synuclein regulates the uptake of vesicular dopamine, and a breakdown in this process allows the build-up of dopamine in the cytoplasm. Dopamine coordinates iron and induces the formation of ROS. Destabilization of the active site of SOD allows a corruption of this antioxidant enzyme such that it becomes pro-oxidant.

  • Excitotoxicity is a downstream consequence of calcium dysregulation as a result of unregulated ROS. Drugs targeting this toxicity (Memantine in AD, Amantadine in PD and Riluzole in ALS) have modest clinical benefit. The antioxidant α-tocopherol has shown clinical promise against AD. Inhibiting metal-mediated redox processes has shown benefit in mouse models of AD and PD and encouraging promise in a small Phase II clinical trial for AD.

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Affiliations

  1. Department of Pathology, The University of Melbourne, and The Mental Health Research Institute of Victoria, Victoria 3010, Australia.

    • Kevin J. Barnham
    • , Colin L. Masters
    •  & Ashley I. Bush
  2. Laboratory for Oxidation Biology, Genetics and Aging Research Unit and Department of Psychiatry, Harvard Medical School, Massachusetts General Hospital East, Charlestown, Massachusetts 02129, USA.

    • Ashley I. Bush

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Competing interests

The authors are shareholders and paid consultants to Prana Biotechnology Ltd. C.L. Masters and A.I. Bush are on the scientific advisory board of Prana Biotechnology Ltd.

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Correspondence to Ashley I. Bush.

Glossary

HIPPOCAMPUS

A region of the brain consisting of the grey matter at the bottom of the lateral ventricle that is involved in motivation, emotion and the formation of memory.

REDOX

A reversible chemical reaction in which one reaction is an oxidation reaction and the reverse a reduction.

FENTON REACTION

Mn+ + H2O2 → M(n+1)+ + OH + OH

AMYLOID

Protein/peptide deposited in diseased tissue, with high β-sheet structure.

NEUROPILE

The mass of closely packed nerve cell processes comprising the central part of a ganglion.

DEMENTIA

Mental deterioration of organic or functional origin.

SUBSTANTIA NIGRA

A small area of the brain containing a cluster of dark-pigmented nerve cells that produces dopamine for neurotransmission.

CORTEX

The unmyelinated neurons (the grey matter) forming the outer layer of the cerebrum.

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