Review Article

Iron, brain ageing and neurodegenerative disorders

  • Nature Reviews Neuroscience volume 5, pages 863873 (2004)
  • doi:10.1038/nrn1537
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Abstract

There is increasing evidence that iron is involved in the mechanisms that underlie many neurodegenerative diseases. Conditions such as neuroferritinopathy and Friedreich ataxia are associated with mutations in genes that encode proteins that are involved in iron metabolism, and as the brain ages, iron accumulates in regions that are affected by Alzheimer's disease and Parkinson's disease. High concentrations of reactive iron can increase oxidative-stress induced neuronal vulnerability, and iron accumulation might increase the toxicity of environmental or endogenous toxins. By studying the accumulation and cellular distribution of iron during ageing, we should be able to increase our understanding of these neurodegenerative disorders and develop new therapeutic strategies.

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Entrez Gene

  1. DCT1

    • DCYTB

      • HFE

        • IREG1

          • PANK2

            • TF

              • TFR

                • Parkinson disease

                  • Alzheimer disease

                    Acknowledgements

                    The authors thank C. Bellei for skillful assistance. M.B.H.Y. was supported by the National Parkinson Foundation (Miami, Florida, USA). M.B.H.Y. and L.Z. acknowledge the support of the Michael J. Fox Foundation (New York, USA). L.Z. was also supported by the Italian Fund for Basic Science (FIRB-MIUR) and the Parkinson's Disease Foundation (New York, USA). J.R.C. acknowledges the support of the Alzheimer's Association, the National Institutes of Health, the Jane B. Barsumian Trust Fund and the G.M. Leader Family.

                    Author information

                    Affiliations

                    1. Institute of Biomedical Technologies-Italian National Research Council, 20090 Segrate (Milano), Italy.

                      • Luigi Zecca
                    2. Technion-Rappaport Faculty of Medicine and Rappaport Institute, Eve Topf and US National Parkinson Foundation Centers of Excellence for Neurodegenerative Diseases, Haifa, Israel.

                      • Moussa B. H. Youdim
                    3. Clinical Neurochemistry and US National Parkinson Foundation Center, Clinic for Psychiatry and Psychotherapy, University of Würzburg, Würzburg, Germany.

                      • Peter Riederer
                    4. Penn State College of Medicine, M.S. Hershey Medical Center, Hershey, Pennsylvania, USA.

                      • James R. Connor
                    5. Unit of Biochemistry, Catholic University of Louvain, Louvain-la-Neuve, Belgium.

                      • Robert R. Crichton

                    Authors

                    1. Search for Luigi Zecca in:

                    2. Search for Moussa B. H. Youdim in:

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                    Competing interests

                    M.B.H.Y. has financial interests in Varinel Inc. (Philadelphia, USA) — the company that is developing the iron chelators VK-28, HLA and M30 — and in Teva Pharmaceutical Industries Ltd (Israel), which is developing the Parkinson-therapeutic drug Rasagiline (and has received a letter of approval for this drug from the United States Food and Drug Administration). To date he has not received any financial reward from them. The other authors all have no competing financial interests.

                    Corresponding author

                    Correspondence to Luigi Zecca.

                    Glossary

                    HAEMOCHROMATOSIS

                    An iron-overload disorder, in which an excessive amount of iron is absorbed from the diet. The iron accumulates in various organs, including the liver, pancreas and heart, which can lead to severe organ damage.

                    ENDOSOMAL COMPARTMENT

                    A system of organelles that carry materials that have been ingested by endocytosis, and pass them to lysosomes for degradation, or recycle them to the cell surface.

                    MICROGLIA

                    Phagocytic immune cells in the brain that engulf and remove cells that have undergone apoptosis.

                    SUBSTANTIA NIGRA

                    A part of the midbrain that contains dopamine-producing neurons, the axons of which innervate the striatum and thereby control body movements.

                    LOCUS COERULEUS

                    A nucleus of the brainstem that is the main supplier of noradrenaline to the brain.

                    CHOROID PLEXUS

                    A site of production of cerebrospinal fluid in the adult brain. It is formed by the invagination of ependymal cells into the ventricles, which become richly vascularized.

                    PUTAMEN/CAUDATE NUCLEUS

                    Two of the components of the striatum, a subpallidal structure that also includes the nucleus accumbens and the olfactory tubercle.

                    GLOBUS PALLIDUS

                    The medial part of the lentiform nucleus, which is one of the components of the basal ganglia.

                    LEWY BODIES

                    Intraneuronal inclusion bodies that form one of the pathological hallmarks of Parkinson's disease. They consist of a dense granular core that is surrounded by a halo of radiating filaments. Their main protein components include α-synuclein and ubiquitin.

                    UBIQUITIN

                    A molecule that is attached to lysine residues of other proteins, often as a tag for their rapid cellular degradation by the proteasome.

                    REACTIVE OXYGEN SPECIES

                    (ROS) Oxygen radicals that are produced by the mitochondrial respiratory chain. In excess, they can cause intracellular and mitochondrial damage, which promotes cell death.

                    TAU

                    A neuronal protein that binds to microtubules, promoting their assembly and stability. It is also a component of neurofibrillary tangles, which are one of the pathological hallmarks of Alzheimer's disease.

                    DYSTONIA

                    A movement disorder that is characterized by abnormal muscle tone.

                    WILSON'S DISEASE

                    A genetic disorder that causes excessive copper accumulation in the liver and brain, resulting in hepatitis and psychiatric and neurological symptoms.