To elucidate the role of the synaptic protein alpha-synuclein in neurodegenerative disorders, transgenic mice expressing wild-type human alpha-synuclein were generated. Neuronal expression of human alpha-synuclein resulted in progressive accumulation of alpha-synuclein-and ubiquitin-immunoreactive inclusions in neurons in the neocortex, hippocampus, and substantia nigra. Ultrastructural analysis revealed both electron-dense intranuclear deposits and cytoplasmic inclusions. These alterations were associated with loss of dopaminergic terminals in the basal ganglia and with motor impairments. These results suggest that accumulation of wild-type alpha-synuclein may play a causal role in Parkinson's disease and related conditions.

The precursor of non-amyloid beta protein component of Alzheimer's disease amyloid (NACP/alpha-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/alpha-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/alpha-synuclein aggregation. Immunoblot analysis showed that human NACP/alpha-synuclein (but not beta-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/alpha-synuclein in the presence of hydrogen peroxide. NACP/ alpha-synuclein aggregates displayed strong thioflavine-S and congo-red reactivity, reminiscent of amyloid. This study suggests that NACP/alpha-synuclein aggregation might be closely related to oxidative reactions which may play a critical role in neurodegeneration in disorders with Lewy bodies.

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␣-Synuclein is a major component of aggregates forming amyloid-like fibrils in diseases with Lewy bodies and other neurodegenerative disorders, yet the mechanism by which ␣-synuclein is intracellularly aggregated during neurodegeneration is poorly understood. Recent studies suggest that oxidative stress reactions might contribute to abnormal aggregation of this molecule. In this context, the main objective of the present study was to determine the potential role of the heme protein cytochrome c in ␣-synuclein aggregation. When recombinant ␣-synuclein was coincubated with cytochrome c/hydrogen peroxide, ␣-synuclein was concomitantly induced to be aggregated. This process was blocked by antioxidant agents such as N-acetyl-L-cysteine. Hemin/ hydrogen peroxide similarly induced aggregation of ␣-synuclein, and both cytochrome c/hydrogen peroxideand hemin/hydrogen peroxide-induced aggregation of ␣-synuclein was partially inhibited by treatment with iron chelator deferoxisamine. This indicates that ironcatalyzed oxidative reaction mediated by cytochrome c/hydrogen peroxide might be critically involved in promoting ␣-synuclein aggregation. Furthermore, double labeling studies for cytochrome c/␣-synuclein showed that they were colocalized in Lewy bodies of patients with Parkinson's disease.Taken together, these results suggest that cytochrome c, a well known electron transfer, and mediator of apoptotic cell death may be involved in the oxidative stressinduced aggregation of ␣-synuclein in Parkinson's disease and related disorders.