Aberrant aggregation of α-synuclein (α-syn) to form fibrils and insoluble aggregates has been implicated in the pathogenic processes of many neurodegenerative diseases. Despite the dramatic effects of dopamine in inhibiting the formation of α-syn fibrils by stabilization of oligomeric intermediates in cell-free systems, no studies have examined the effects of intracellular dopamine on α-syn aggregation. To study this process and its association with neurodegeneration, intracellular catechol levels were increased to various levels by expressing different forms of tyrosine hydroxylase, in cells induced to form α-syn aggregates. The increase in the steady-state dopamine levels inhibited the formation of α-syn aggregates and induced the formation of innocuous oligomeric intermediates. Analysis of transgenic mice expressing the disease-associated A53T mutant α-syn revealed the presence of oligomeric α-syn in nondegenerating dopaminergic neurons that do contain insoluble α-syn. These data indicate that intraneuronal dopamine levels can be a major modulator of α-syn aggregation and inclusion formation, with important implications on the selective degeneration of these neurons in Parkinson's disease.
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