Copper(II)-induced self-oligomerization of alpha-synuclein

alpha-Synuclein is a component of the abnormal protein depositions in senil e plaques and Lewy bodies of Alzheimer's disease (AD) and Parkinson's disea se respectively. The protein was suggested to provide a possible nucleation centre for plaque formation in AD via selective interaction with amyloid b eta/A4 protein (A beta). We have shown previously that alpha-synuclein has experienced self-oligomerization when A beta 25-35 was present in an orient ation-specific manner in the sequence. Here we examine this biochemically s pecific self-oligomerization with the use of various metals. Strikingly, co pper(II) was the most effective metal ion affecting alpha-synuclein to form self-oligomers in the presence of coupling reagents such as dicyclohexylca rbodi-imide or N-(ethoxycarbonyl)-2-ethoxy- 1,2-dihydroquinoline, The size distribution of the oligomers indicated that monomeric alpha-synuclein was oligomerized sequentially. The copper-induced oligomerization was shown to be suppressed as the acidic C-terminus of alpha-synuclein was truncated by treatment with endoproteinase Asp-N. In contrast, the A beta 25-35-induced oligomerizations of the intact and truncated forms of alpha-synuclein were not affected. This clearly indicated that the copper-induced oligomerizatio n was dependent on the acidic C-terminal region and that its underlying bio chemical mechanism was distinct from that of the A beta 25-35-induced oligo merization. Although the physiological or pathological relevance of the oli gomerization remains currently elusive, the common outcome of alpha-synucle in on treatment with copper or A beta 25-35 might be useful in understandin g neurodegenerative disorders in molecular terms. In addition, abnormal cop per homoeostasis could be considered as one of the risk factors for the dev elopment of disorders such as AD or Parkinson's disease.