One of the defining characteristics of
neurodegenerative diseases, including Parkinson's, Alzheimer's and Huntington's diseases, is abnormal accumulations of
iron, specifically in affected areas. Following injection of
iron in rat brains, a relatively selective lesion of dopamine neurons, similar to
parkinsonism, occurs. These observations indicate that Fe(II)-mediated generation of
free radical species, by the Fenton reaction, might contribute to the pathoetiology of these diseases.
Iron is known to possess multiple roles in the biosynthesis of
catecholamines in dopaminergic neurons. These include, as Fe(II), facilitating the production of
dopamine from
phenylalanine by
tyrosine hydroxylase, and as
heme, assisting the recycling of ascorbate by
cytochrome b-561 required for the generation of
norepinephrine from
dopamine by
dopamine beta-hydroxylase. In this study, it is demonstrated that a human and mouse gene product, stromal cell-derived receptor 2, is a homologue of
cytochrome b-561 and duodenal
cytochrome b, and is thus predicted to be active as a
ferric reductase. Moreover, this
protein also contains a domain homologous to the N-terminal regulatory region of
dopamine beta-hydroxylase. These findings from sequence analysis lead to a prediction that stromal cell-derived receptor 2 is a
catecholamine-regulated
ferric reductase active in the brain. Dysfunction of
cytochrome b-561 or stromal cell-derived receptor 2, therefore, might predispose individuals to abnormal accumulation of Fe(III) and/or generation of cytotoxic
free radicals as a consequence of a rapid cycling between Fe(III) and Fe(II). The hypothesis that aberrant
ferric reductase activities are involved in the progression of
neurodegenerative diseases should open up new avenues of research, and possibly
therapy, for these devastating diseases.