Abstract
Parkinson's disease (PD) is characterized by selective and progressive degeneration of dopamine (DA)-producing neurons in the substantia nigra pars compacta (SNpc) and by abnormal aggregation of α-synuclein. Previous studies have suggested that DA can interact with α-synuclein, thus modulating the aggregation process of this protein; this interaction may account for the selective vulnerability of DA neurons in patients with PD. However, the relationship between DA and α-synuclein, and the role in progressive degeneration of DA neurons remains elusive. We have shown that in the presence of DA, recombinant human α-synuclein produces non-fibrillar, SDS-resistant oligomers, while β-sheet-rich fibril formation is inhibited. Pharmacologic elevation of the cytoplasmic DA level increased the formation of SDS-resistant oligomers in DA-producing neuronal cells. DA promoted α-synuclein oligomerization in intracellular vesicles, but not in the cytosol. Furthermore, elevation of DA levels increased secretion of α-synuclein oligomers to the extracellular space, but the secretion of monomers was not changed. DA-induced secretion of α-synuclein oligomers may contribute to the progressive loss of the dopaminergic neuronal population and the pronounced neuroinflammation observed in the SNpc in patients with PD.
Highlights
Parkinson’s disease (PD) is an age-related, progressive neurodegenerative disorder characterized by motor abnormalities, such as resting tremors, bradykinesia, and rigidity (Fahn and Sulzer, 2004)
Size exclusion chromatography (SEC) revealed that the formation of non-fibrillar oligomeric aggregates was increased in the presence of DA (Figure 2A)
Primary symptoms of PD are attributed to the selective loss of DA neurons in the substantia nigra pars compacta (SNpc) of the ventral midbrain
Summary
Parkinson’s disease (PD) is an age-related, progressive neurodegenerative disorder characterized by motor abnormalities, such as resting tremors, bradykinesia, and rigidity (Fahn and Sulzer, 2004) Such parkinsonian motor symptoms are attributed to selective loss of pigmented, dopaminergic neurons in the substantia nigra pars compacta (SNpc) in the midbrain (Fahn and Sulzer, 2004). Critical evidence linking α-synuclein aggregation to PD has accumulated from the finding of missense mutations and the multiplication of the α-synuclein gene in rare forms of early-onset PD (Farrer, 2006). All of these mutations result in accelerated formation of one or more forms of aggregates in the process of fibrillation (Kim and Lee, 2008)
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