Dopamine complexes of iron in the etiology and pathogenesis of Parkinson's disease

Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimers. The main pathological hallmark of Parkinson's is the deterioration and death of neurons that produce the neurotransmitter dopamine. Much of the neuronal damage takes place in the substantia nigra, a small region of the midbrain that contains the cell bodies of neurons that produce dopamine. The deterioration and death of dopaminergic neurons are directly associated with misfolding and aggregation of proteins, principally a-synuclein, that are natively unfolded. Present also in the substantia nigra is an unusually high concentration of vestigial iron. Protein misfolding in non-genetic (sporadic) cases of PD has been associated with reactive oxygen species formed as products of O-2 reduction by the combination of dopamine and iron. Combinations of Fe3+, dopamine hydrochloride (DA(H+)Cl), and various ancillary ligands have been studied as a function of pH in aqueous solution to determine the optimum pH for complex formation. With ancillary ligands (La) derived from nitrilotriacetic acid and ethylenediamine diacetic acid spectral changes are consistent with the formation of L4Fe(DA(H+)) species that reach a maximum concentration at pH 7.2. With edta as the ancillary ligand, spectral features at pH 7 resemble those of Fe3+-catecholate complexes that contain catecholate ligands bonded through a single oxygen. This demonstrates the ability of the dopamine catechol functionality to penetrate the coordination sphere of even exceptionally stable iron chelates. (c) 2008 Elsevier Inc. All rights reserved.