Exploring the Function of 14-3-3 Proteins in Neurodegenerative Disease

The two pathological hallmarks of Parkinson's are neurodegeneration in the substantia nigra parc compacta and the presence of Lewy bodies in the surviving neurons. Recent evidence indicates that Lewy bodies share biochemical and morphological similarities with aggresomes, a large juxtanuclear aggregate. In previous studies, we observed that 14-3-3 proteins promote the aggresome formation of α-Synuclein, the main component of Lewy bodies. In this study, we determined 14-3-3 to have a generalized aggresome promoting function by examining two known aggregation-prone proteins, including a mutant form of CFTR and the GFP-250 protein. To assess the isoform specificity of 14-3-3 proteins in this process, we compared the extent of increase in aggresome formation promoted by overexpression of two different 14-3-3 isoforms. Furthermore, we utilized two different mutants to demonstrate that dimerization of 14-3-3 may not be required for its function in the aggresome formation cascade. Taken together, our data indicate that 14-3-3 proteins may play essential critical role in the aggresome formation process. The discovery of the mechanism by which 14-3-3 participates in the aggresome formation cascade may help us to understand pathogenesis of neurodegenerative diseases, such as Parkinson's disease.