Oxidative stress induces amyloid-like aggregate formation of NACP/α-synuclein in vitro

Abstract

The precursor of non-amyloid β protein component of Alzheimer's disease amyloid (NACP/α-synuclein), found in Lewy bodies of Parkinson's disease (PD), is a presynaptic protein genetically linked to some familial types PD. Mechanisms of abnormal NACP/α-synuclein aggregation in neurodegenerative diseases are unclear. Since oxidative stress might play a role in PD pathogenesis, we investigated the role of iron and peroxide in NACP/α-synuclein aggregation. Immunoblot analysis showed that human NACP/α-synuclein (but not β-synuclein) aggregated in the presence of ferric ion and was inhibited by the iron chelator deferoxamine. Ferrous ion was not effective by itself, but it potentially aggregated NACP/α-synuclein in the presence of hydrogen peroxide. NACP/α-synuclein aggregates displayed strong thioflavine-S and congo-red reactivity, reminiscent of amyloid. This study suggests that NACP/α-synuclein aggregation might be closely related to oxidative reactions which may play a critical role in neurodegeneration in disorders with Lewy bodies.