Alpha-synuclein and dopamine metabolism.

alpha-Synuclein (alpha-Syn), a 140-amino-acid protein richly expressed in presynaptic terminals in the central nervous system, has been shown to play a central role in the pathogenesis of Parkinson's disease. Although the normal functions of alpha-Syn remain elusive, accumulating evidence shows that the molecule is involved in multiple steps related to dopamine metabolism, including dopamine synthesis, storage, release, and uptake. The regulatory effect of alpha-Syn on dopamine metabolism is likely to tone down the amount of cytoplasmic dopamine at nerve terminals, thereby limiting its conversion to highly reactive oxidative molecules. Formation of alpha-Syn protofibrils triggered by factors such as gene mutations and environmental toxins can make the molecule lose its normal functions, leading to disrupted homeostasis of dopamine metabolism, increased cytoplasmic dopamine levels, and enhanced oxidative stress in dopaminergic neurons. The enhanced oxidative stress will, in turn, exacerbate the formation of alpha-Syn protofibrils and drive the neurons into a vicious cycle, which will finally result in the selective degeneration of the dopaminergic neurons associated with Parkinson's disease.