The role of astroglial iron in the pathogenesis of Parkinson's disease /

The excessive deposition of redox-active iron has been amply documented in the basal ganglia of subjects with Parkinson's disease (PD). Yet, much remains to be learned regarding the cellular and subcellular distribution of this metal and the precise role(s) it plays in the pathogenesis of PD. Cysteamine (CSH) induces the appearance of peroxidase-positive cytoplasmic granules in cultured neonatal rat astroglia which are identical to glial inclusions that progressively accumulate in the aging subcortical brain. These inclusions are derived from degenerate mitochondria which sequester iron and other transition metals before undergoing fusion with lysosomes in an autophagic process. Dr. Schipper has previously demonstrated that iron-mediated peroxidase activity in these cells is capable of oxidizing dopamine and other catechols to potentially neurotoxic semiquinone radicals (Schipper et al., 1991). In the present study, we co-cultured PC12 cells, a catecholamine-secreting cell line, atop confluent monolayers of either CSH pre-treated (iron-enriched) or control neonatal rat astroglia. We observed that the PC12 cells grown on the surface of iron enriched (senescent-like) astroglia were far more susceptible to dopamine/H2O 2-related killing than PC12 cells cultured atop control glial substrata. Augmented killing of PC12 cells in the former paradigm was inhibited by the antioxidants, ascorbate, melatonin or resveratrol implicating a free radical mechanism of action. The aging-associated accumulation of iron in mitochondria of subcortical astroglia may facilitate the oxidation of dopamine to neurotoxic free radical intermediates and thereby predispose the senescent nervous system to PD and other neurodegenerative afflictions