The nuclear accumulation of alpha-synuclein is mediated by importin alpha and promotes neurotoxicity by accelerating the cell cycle

alpha-Synuclein (alpha-syn), a 14 kDa pre-synaptic protein, is widely involved in the Parkinson's disease (PD) pathogenesis. Recent studies have shown that the nuclear accumulation of alpha-syn might have a toxic effect. The main purpose of the present study was to explore which amino acid residues in alpha-syn are associated with its nuclear accumulation, the molecule(s) mediated the nuclear import of alpha-syn, and the role of alpha-syn accumulated in the nucleus. It has been noted that the nuclear import of alpha-syn may be mediated by importin alpha and that both the amino acid residues 1-60 and 103-140 of alpha-syn were indispensable for its nuclear import. After imported into the nucleus, the accumulated alpha-syn played a toxic role in both the PC12 cells and the C57 mice. Furthermore, alpha-syn-nuclear localization signal-injected mice showed behavioral symptoms associated with PD. Further studies performed in vitro showed that the toxicity of alpha-syn in the nucleus might be due to an interference of the cell cycle. Thus, it can be concluded that alpha-syn can accumulate in nucleus, which is mediated by importin alpha, and promote neurotoxicity by accelerating the cell cycle. (C) 2013 Elsevier Ltd. All rights reserved.