alpha-Synuclein shares physical and functional homology with 14-3-3 proteins

alpha-Synuclein has been implicated in the pathophysiology of many neurodeg enerative diseases, including Parkinson's disease (PD) and Alzheimer's dise ase. Mutations in alpha-synuclein cause some cases of familiar PD (Polymero poulos et at., 1997; Kruger et al., 1998). In addition, many neurodegenerat ive diseases show accumulation of alpha-synuclein in dystrophic neurites an d in Lewy bodies (Spillantini et al., 1998). Here, we show that alpha-synuc lein shaves physical and functional homology with 14-3-3 proteins, which ar e a family of ubiquitous cytoplasmic chaperones. Regions of alpha-synuclein and 14-3-3 proteins share over 40% homology. In addition, alpha-synuclein binds to 14-3-3 proteins, as well as some proteins known to associate with 14-3-3, including protein kinase C, BAD, and extracellular regulated kinase , but not Raf-l. We also show that overexpression of alpha-synuclein inhibi ts protein kinase C activity. The association of alpha-synuclein! with BAD and inhibition of protein kinase C suggests that increased expression of al pha-synuclein could be harmful. Consistent with this hypothesis, we observe d that overexpression of wild-type alpha-synuclein is toxic, and overexpres sion of alpha-synuclein containing the A53T or A30P mutations exhibits even greater toxicity. The activity and binding profile of alpha-synuclein sugg ests that it might act as a protein chaperone and that accumulation of alph a-synuclein could contribute to cell death in neurodegenerative diseases.