INVESTIGATION OF THE SYNERGIC EFFECT OF β-SYNUCLEIN WITH HSP27 ON NEUROPROTECTION

β-突触核蛋白与 HSP27 神经保护协同作用的研究

• 批准号: 17300115
• 负责人: HASHIMOTO Makoto
• 金额: $ 7.92万
• 依托单位: Tokyo Metropolitan Organization for Medical Research
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-17300115/
• 关键词: SYNUCLEINOPATHY; NEURODEGENERRATION; GENE MUTATION; α-SYNUCLEIN; β-SYNUCLEIN; LYSOSOME; TRANSGENIC MICE; BASAL GANGLIA; シヌクレイノパチー; シヌクレイン; パーキンソン病; レビー小体; 蛋白凝集; アミロイド; ルイ小体; DJ-1

TWO MISSENSE MUTATIONS (P123H AND V70M) OF BETA-SYNUCLEIN, THE HOMOLOGUE OF ALPHA-SYNUCLEIN, HAVE BEEN RECENTLY IDENTIFIED IN DEMENTIA WITH LEWY BODIES, HOWEVER, THE MECHANISM THROUGH WHICH THESE MUTATIONS INFLUENCE THE PATHOGENESIS OF DEMENTIA WITH LEWY BODIES IS UNCLEAR, TO INVESTIGATE THE ROLE OF THE BETA-SYNUCLEIN MUTATIONS IN NEURODEGENERATION, EACH MUTANT WAS STABLY TRANSFECTED INTO B103 NEUROBLASTOMA CELLS CELLS OVEREXPRESSING MUTATED BETA-SYNUCLEIN HAD ENHANCED LYSOSOMAL, ACTIVITY AND LYSOSOMAL INCLUSION BODIES IN THE CYTOPLASM, SUGGESTING THAT THESE MISSENSE MUTATIONS OF BETA_SYNUCLEIN MIGHT PLAY A CAUSATIVE ROLE IN STIMULATING NEURODEGENETION. SUBSEQUENTLY, WE CREATED TRANSGENIC MICE OVEREXPRESSING P123H BETA-SYNUCLEIN USING THY-1 PROMOTER. THE MICE EXHIBITED AXONAL DEGENERATION AND SYNAPTIC TERMINAL SWELLING, ASSOCIATED WITH PROTEIN AGGREGATION AND BEHAVIOURAL ABNORMALITIES, INCLUDING MOTER DYSFUNCTION. THUS, THESE TRANSGENIC MICE MAY BE USEFUL AS NEW SYNUCLEINOPATHY MODEL MICE. FURTHER STUDY IS IN PROGRESS, INCLUDING CREATION OF BIGENIC MICE BETWEEN P123H BETA-SYNUCLEIN TRANSGENIC MICE AND ALPHA-SYNUCLEIN TRANSGENIC MICE.

最近在伴路易体痴呆中发现了α -突触核蛋白的同源物- β -突触核蛋白的两个错义突变（p123h和v70m），然而，这些突变影响伴路易体痴呆发病机制的机制尚不清楚，为了研究β -突触核蛋白突变在神经变性中的作用，将每个突变体稳定转染到b103神经母细胞瘤细胞中，过表达突变的β -突触核蛋白增强了溶酶体。细胞质中的活性和溶酶体包涵体，表明这些β -突触核蛋白错义突变可能在刺激神经变性中起致因作用。随后，我们利用它们-1启动子构建了过表达p123h β -突触核蛋白的转基因小鼠。小鼠表现出轴突变性和突触末端肿胀，与蛋白质聚集和行为异常有关，包括母亲功能障碍。因此，这些转基因小鼠可作为新的突触核蛋白病模型小鼠。进一步的研究正在进行中，包括在p123h β -突触核蛋白转基因小鼠和α -突触核蛋白转基因小鼠之间建立双基因小鼠。

项目成果

Distinct distribution of a- and b-synuclein in neural and non-neural tissues in wild type mouse.

野生型小鼠神经和非神经组织中 a-和 b-突触核蛋白的不同分布。

• 发表时间: 2006
• 作者: Nakai;M;et. al.
• 通讯作者: et. al.

Enhanced lysosomal pathology caused by beta-synuclein mutants linked to dementia with Lewy body.

β-突触核蛋白突变体引起的溶酶体病理增强与路易体痴呆有关。

• 发表时间: 2007
• 作者: Snyder H;et. al.;藤田 雅代;Eliezer Masliah;Hashimoto M
• 通讯作者: Hashimoto M

Molecular mechanism for the inverse incidence of of Parkinson's disease and cancer : Synuclein as stimulator of tumour differentiation.

帕金森病和癌症发病率相反的分子机制：突触核蛋白作为肿瘤分化的刺激剂。

• 发表时间: 2006
• 作者: Hashimoto;M.
• 通讯作者: M.

beta-Synuclein reduces proteasomal inhibition by alpha-synuclein but not gamma-synuclein.

β-突触核蛋白可减少 α-突触核蛋白对蛋白酶体的抑制，但不会减少 γ-突触核蛋白。

• 发表时间: 2005
• 期刊: J Biol Chem 280
• 作者: Nakai M;et. al.;Fujita M;Bar-ON P;Fujita M;Bar-On P;Waragai M;藤田 雅代;Shults C;Snyder H
• 通讯作者: Snyder H

High beta-secretase activity elicits neurodegeneration in transgenic mice despite reductions in amyloid-beta levels.

尽管β-淀粉样蛋白水平降低，但高β-分泌酶活性仍会引起转基因小鼠的神经变性。

• 发表时间: 2005
• 期刊: J Biol Chem 280
• 作者: Rockenstein E;et. al.
• 通讯作者: et. al.