title: The nuclear accumulation of alpha-synuclein is mediated by importin alpha and promotes neurotoxicity by accelerating the cell cycle.
abstract: α-Synuclein (α-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 α-syn might have a toxic effect. The main purpose of the present study was to explore which amino acid residues in α-syn are associated with its nuclear accumulation, the molecule(s) mediated the nuclear import of α-syn, and the role of α-syn accumulated in the nucleus. It has been noted that the nuclear import of α-syn may be mediated by importin α and that both the amino acid residues 1-60 and 103-140 of α-syn were indispensable for its nuclear import. After imported into the nucleus, the accumulated α-syn played a toxic role in both the PC12 cells and the C57 mice. Furthermore, α-syn-nuclear localization signal-injected mice showed behavioral symptoms associated with PD. Further studies performed in vitro showed that the toxicity of α-syn in the nucleus might be due to an interference of the cell cycle. Thus, it can be concluded that α-syn can accumulate in nucleus, which is mediated by importin α, and promote neurotoxicity by accelerating the cell cycle.
authors: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Department of Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, PR China; Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming 650118, PR China.
authors: Kai-Li
authors: KL
authors: Ma
authors: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Department of Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, PR China.
authors: Lian-Kun
authors: LK
authors: Song
authors: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Department of Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, PR China.
authors: Yu-He
authors: YH
authors: Yuan
authors: Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming 650118, PR China.
authors: Ying
authors: Y
authors: Zhang
authors: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Department of Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, PR China.
authors: Ning
authors: N
authors: Han
authors: Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, PR China.
authors: Kai
authors: K
authors: Gao
authors: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Department of Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, PR China. Electronic address: chennh@imm.ac.cn.
authors: Nai-Hong
authors: NH
authors: Chen
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000502:physiology; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology*; D002467:Cell Nucleus / Q000187:drug effects / Q000502:physiology*; D059290:Dopaminergic Neurons / Q000000981:diagnostic imaging / Q000502:physiology; D005947:Glucose / Q000378:metabolism; D008810:Mice, Inbred C57BL; D020258:Neurotoxicity Syndromes / Q000503:physiopathology; D016716:PC12 Cells; D011877:Radionuclide Imaging; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012402:Rotenone / Q000633:toxicity; D013378:Substantia Nigra / Q000000981:diagnostic imaging / Q000503:physiopathology; D014162:Transfection; D014475:Uncoupling Agents / Q000633:toxicity; D028901:alpha Karyopherins / Q000378:metabolism*; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: D011993:Recombinant Fusion Proteins; C497604:SNCA protein, human; C497605:Snca protein, mouse; D014475:Uncoupling Agents; D028901:alpha Karyopherins; D051844:alpha-Synuclein; D012402:Rotenone; D005947:Glucose
keywords: Cell cycle; Importin α; Neurotoxicity; Nuclear accumulation; α-Synuclein