The role of alpha-synuclein in central nervous system physiology and neurodegenerative disorders

alpha-synuclein is a molecule which has been shown to be important for two major neurodegenerative diseases, these being Alzheimer's Disease and Parkinson's Disease. Since its discovery in 1988, most of the research thus far has focused on the characterization of alpha-synuclein as a component of the hallmark pathological lesions of these diseases, either the amyloid plaque or the lewy body. Little is known about the biology of alpha-synuclein at the molecular level and even less is known about the role that alpha-synuclein might have in the healthy physiological state. We have obtained structural data of the recombinant alpha-synuclein molecule via Nuclear Magnetic Resonance and Circular Dichroism studies which shows that alpha-synuclein is natively unfolded. We also have conducted a number of experiments which show the effect of pH, temperature, and time on the aggregation properties of alpha-synuclein. In addition, we examined the developmental expression of alpha-synuclein in murine brain development via ribonuclease protection assay, western blotting, and immunocytochemistry. This data suggested that alpha-synuclein is likely important for neurogenesis and synaptogenesis. Furthermore, we observed a differential distribution of alpha-synuclein in the cytosolic and membrane-associated fractions. Finally, using the GT1-7 murine hypothalamic tumor cell line, we have established a cell culture model whereby we propose a previously unreported association of alpha-synuclein with the mitochondria. In cells overexpressing alpha-synuclein, we observe formation of megamitochondria, increased oxidative stress, increased glutathione activity, decreased mitochondrial activity, and decreased mitochondrial membrane potential. We also observe that the primary secretory function of these cells is compromised. In addition, many of these alterations can be ameliorated with the pretreatment of these cells with vitamin E. Hence, we suggest that alpha-synuclein may be important for mitochondrial function, and the mechanistic explanation may be related to the enzyme complexes of the respiratory chain.