Alpha-Synuclein Is a Cellular Ferrireductase

alpha-synuclein (alpha S) is a cellular protein mostly known for the association of its aggregated forms with a variety of diseases that include Parkinson's disease and Dementia with Lewy Bodies. While the role of alpha S in disease is well documented there is currently no agreement on the physiological function of the normal isoform of the protein. Here we provide strong evidence that alpha S is a cellular ferrireductase, responsible for reducing iron (III) to bio available iron (II). The recombinant form of the protein has a V-Max of 2.72 nmols/min/mg and K-m 23 mu M. This activity is also evident in lysates from neuronal cell lines overexpressing alpha S. This activity is dependent on copper bound to alpha S as a cofactor and NADH as an electron donor. Overexpression of alpha-synuclein by cells significantly increases the percentage of iron (II) in cells. The common disease mutations associated with increased susceptibility to PD show differences in activity or iron (II) levels. This discovery may well provide new therapeutic targets for PD and Lewy body dementias.