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Nat Struct Mol Biol:加重阿尔茨海默症和帕金森病的竟是同样的酶

2017-07-05 佚名 生物探索

阿尔茨海默症和帕金森病是不一样的。它们影响着大脑的不同区域,遗传和环境的危险因素也明显有区别。帕金森病有运动功能障碍,双手振颤,抬不起,迈不开步,直不起腰等症状。阿尔茨海默症最主要症状是记忆差,严重时分不清子女,不认路,人格出现障碍,但运动功能正常。 但在生化水平上,这两种神经退行性疾病竟然看起来相似。这是Emory大学Keqiang Ye博士所领导的科研团队,在寻找帕金森病一个潜在的药物靶点时

阿尔茨海默症和帕金森病是不一样的。它们影响着大脑的不同区域,遗传和环境的危险因素也明显有区别。帕金森病有运动功能障碍,双手振颤,抬不起,迈不开步,直不起腰等症状。阿尔茨海默症最主要症状是记忆差,严重时分不清子女,不认路,人格出现障碍,但运动功能正常。
但在生化水平上,这两种神经退行性疾病竟然看起来相似。这是Emory大学Keqiang Ye博士所领导的科研团队,在寻找帕金森病一个潜在的药物靶点时所发现的。相关文章于7月3日在线发表在Nature Structural and Molecular Biology上。

1阿尔茨海默症和帕金森都有粘性蛋白积累

在阿尔茨海默症(AD)和帕金森病(PD)中,一种粘性蛋白在脑细胞中形成有毒的团块。在阿尔茨海默症中,细胞内的麻烦制造者被称为Tau蛋白,使神经原纤维缠结。在帕金森氏病,粘蛋白是α-突触核蛋白,形成了Lewy小体。

Ye和他的同事已经发现了一种酶(天冬酰胺内肽酶或称AEP)会修饰Tau蛋白让它更具有粘性和毒性。阻断AEP的药物在阿尔茨海默症的动物模型中体现出有益的效果。文章以“Cleavage of tau by asparagine endopeptidase mediates the neurofibrillarypathology in Alzheimer’s disease”为题发表在2014年的Nature Medicine 上。

2帕金森氏病人样本中有AEP酶产生的片段

在2017年新发表的文章中,Emory大学的研究团队揭示了AEP也是以同样的方式作用于帕金森氏病的α-突触核蛋白。

Ye博士介绍说:“在帕金森氏病中α-突触核蛋白的表现很像阿尔茨海默氏症中的Tau。我们认为如果AEP修剪Tau,它也很可能会修剪α-突触核蛋白。”

Ye博士的团队发现在帕金森氏病人的脑组织样本中可以发现AEP剪刀产生的特有的α-突触核蛋白片段,而对照样本中却没有。AEP在年龄依赖的机制中被活化,在N103位点切割人的α-突触核蛋白。

在对照的大脑样本中AEP局限于溶酶体,这个处理“垃圾”的细胞器中。但在帕金森病人的样本中,AEP从溶酶体中泄漏出来,到了细胞的其余部分。

3在小鼠大脑表达和抑制该片段证明了其作用

研究人员发现由AEP产生的α-突触核蛋白片段比全长蛋白更容易聚集成团,在小鼠的大脑中存在时毒性更大。在小鼠大脑的黑质中过表达AEP切割的α-突触核蛋白1-103的话,会造成多巴胺神经元的损失和运动缺陷。此外α-突触核蛋白突变为AEP不能切割它的状况时,毒性较低。抑制 AEP介导对α-突触核蛋白的切割时,会减少α-突触核蛋白的病理作用。这些发现支持AEP在α-突触核蛋白为关键介质的帕金森病中的作用。

Ye博士提醒说AEP不是能将α-突触核蛋白切割成有毒片段的唯一的酶,全长α-突触核蛋白仍能聚集并造成伤害。但是,他说他的团队正在帕金森病的动物模型中测试用药物抑制AEP的效果。

原始出处:
Zhentao Zhang, Seong Su Kang, Xia Liu,et al.Asparagine endopeptidase cleaves α-synuclein and mediates pathologic activities in Parkinson's disease.Nat Struct Mol Biol.03 July 2017.doi:10.1038/nsmb.3433

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    2017-09-06 sunylz
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  4. 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    2017-09-25 liye789132251
  5. 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  6. 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createdAvatar=https://wx.qlogo.cn/mmopen/Q3auHgzwzM4o2XVpJ6449yqDsjibydI5HnJ8MibGxNn4HZiaZib0bdfibbwoz3KQrIyN9AGxq36ZlZRNicYlPfOOWMtwgsajY6mGNFiaPclFdowjD0/0, createdBy=97bd1338592, createdName=清风拂面, createdTime=Wed Jul 05 14:22:08 CST 2017, time=2017-07-05, status=1, ipAttribution=)]
    2017-09-23 日月
  7. 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encodeId=e0d91e95131ee, content=<a href='/topic/show?id=1c9f16846fe' target=_blank style='color:#2F92EE;'>#Struc#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=45, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=16846, encryptionId=1c9f16846fe, topicName=Struc)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=4a4d285, createdName=日月, createdTime=Sat Sep 23 04:13:00 CST 2017, time=2017-09-23, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=228759, encodeId=9b83228e59c7, content=AEP酶有粘性,能促使α-syn和Aβ聚集。正常情况下AEP酶溶酶体中,帕金森病人AEP在溶酶体外, beContent=null, objectType=article, channel=null, level=null, likeNumber=92, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://thirdwx.qlogo.cn/mmopen/vi_32/Q0j4TwGTfTJECOI3z1sgUHAkZmaibc3WatVTwLeT5sK7gFumIunAwEwb5jdSIcr9mFjL0PjUW8emoKChia20o0Qg/132, createdBy=a4ef2100982, createdName=Coco5816, 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    2017-08-01 Coco5816

    AEP酶有粘性,能促使α-syn和Aβ聚集。正常情况下AEP酶溶酶体中,帕金森病人AEP在溶酶体外

    0

  8. 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  9. 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    2017-07-05 清风拂面

    这样好的文章,多多益善

    0

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蒙大拿大学的研究人员进行的一项新研究,经燃烧产生的空气污染颗粒(CDNPs)存在于年轻的城市居民大脑中,这项研究一时间引起了社会人员的高度关注。 研究人员利用透射电子显微镜观察了大量墨西哥城儿童、青少年以及年轻人的神经元、神经胶质细胞、脉络丛和神经血管中存在的污染颗粒,这些人均长期暴露于高于US-EPA标准的污染颗粒中。日前该研究成果发表在《阿尔茨海默病杂志》上。

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