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Acta Neuropathologica: 亨廷顿病中的发育畸形:成人大脑局部神经元迁移缺陷的神经病理学证据

2021-03-21 网络 网络

亨廷顿病(HD)的神经发育异常及其可能引起的神经退行性变越来越受到重视。引起HD的亨廷顿(HTT)基因中的致病性CAG重复扩增从受孕开始就存在,并在整个发育和生命的剩余阶段持续表达。

亨廷顿病(HD)的神经发育异常及其可能引起的神经退行性变越来越受到重视。引起HD的亨廷顿(HTT)基因中的致病性CAG重复扩增从受孕开始就存在,并在整个发育和生命的剩余阶段持续表达。生命健康的发育依赖于基因编码的HTT蛋白,它在原肠胚形成和皮质发生中起着重要作用。

纯合HTT基因敲除小鼠不能发育超过胚胎中期(E7.5-8.5),HTT亚型小鼠表现出神经元迁移缺陷和后期纹状体变性。有限的人类数据表明,基因扩增携带者存在发育差异(GEC)。与年龄匹配的对照组相比,GEC的大脑发育速度降低,颅内体积有缩小的趋势。此外,人类胎儿GEC的大脑在皮质生成方面有广泛的异常。在孕13周时,HTT和连接复合蛋白错误定位于心室区,神经祖细胞表现出各种缺陷,包括细胞极性、分化和纤毛形成的异常。

本研究回顾性分析了纽约脑库(发现队列)和一个独立队列(验证队列),以确定发育畸形是否在HD比非HD大脑中更常见并且记录他们的神经病理学特征。130个HD和1600个非HD全脑被纳入发现队列,720个HD和1989个非HD半脑被纳入验证队列。发育畸形的病例在HD中的检出率是非HD脑的6.4-8.2倍(发现队列:OR 8.68,95%CI 3.48-21.63,P=4.8×10-5;验证队列:OR 6.50,95%CI 1.83-23.17,P=0.0050)。

脑室周围结节性异位症(PNH)是最常见的畸形,含有类似于皮质的HTT和p62聚集物,而具有不成熟神经元群的皮质畸形则不含有这种聚集物。HD畸形患者多为女性,其HTT-CAG杂合性扩增在40~52个重复之间,除1例下丘脑中线错构瘤外,其余均为不对称局灶性。

本研究使用两个独立的脑库队列,神经病理学显示HD脑发育畸形的发生率增加。由于致病性HTT基因扩增与基因组不稳定性有关,一种可能的解释是神经元前体更容易受到参与皮层迁移的基因体细胞突变的影响。而本文研究发现进一步支持了新的证据,即HTT基因的致病性三核苷酸重复扩增可能影响神经发育。

Hickman, R.A., Faust, P.L., Rosenblum, M.K. et al. Developmental malformations in Huntington disease: neuropathologic evidence of focal neuronal migration defects in a subset of adult brains. Acta Neuropathol 141, 399–413 (2021).

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    2022-01-22 yb6560
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    2021-10-28 windight
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  4. 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createdName=windight, createdTime=Thu Oct 28 01:54:49 CST 2021, time=2021-10-28, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1786728, encodeId=93a81e86728fa, content=<a href='/topic/show?id=1c5d13e9171' target=_blank style='color:#2F92EE;'>#pathologic#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=131, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=13791, encryptionId=1c5d13e9171, topicName=pathologic)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=0cd7162, createdName=nakerunner, createdTime=Fri Jun 11 08:54:49 CST 2021, time=2021-06-11, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1640998, encodeId=77ef1640998b3, content=<a href='/topic/show?id=7c99939e3fd' target=_blank style='color:#2F92EE;'>#迁移#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=88, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=93973, 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ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1491398, encodeId=2db8149139863, content=<a href='/topic/show?id=5316e4387aa' target=_blank style='color:#2F92EE;'>#神经病#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=86, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=74387, encryptionId=5316e4387aa, topicName=神经病)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=1ab48885684, createdName=axin012, createdTime=Tue Mar 23 05:54:49 CST 2021, time=2021-03-23, status=1, ipAttribution=)]
  5. [GetPortalCommentsPageByObjectIdResponse(id=1786448, encodeId=daaa1e86448d2, content=<a href='/topic/show?id=569f13e9045' target=_blank style='color:#2F92EE;'>#Pathol#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=137, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=13790, encryptionId=569f13e9045, topicName=Pathol)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=4b65161, createdName=yb6560, createdTime=Sat Jan 22 01:54:49 CST 2022, time=2022-01-22, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1850109, encodeId=7938185010997, content=<a href='/topic/show?id=61815385aa' target=_blank style='color:#2F92EE;'>#CTA#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=0, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=5385, encryptionId=61815385aa, topicName=CTA)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=ec9955, 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channel=null, level=null, likeNumber=96, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=70344, encryptionId=9857e03444b, topicName=畸形)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=ca20190, createdName=wushaoling, createdTime=Tue Mar 23 05:54:49 CST 2021, time=2021-03-23, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1365120, encodeId=608c13651202f, content=<a href='/topic/show?id=c83a2455270' target=_blank style='color:#2F92EE;'>#亨廷顿病#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=88, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=24552, encryptionId=c83a2455270, topicName=亨廷顿病)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=0a8e213, createdName=hongbochen, createdTime=Tue Mar 23 05:54:49 CST 2021, time=2021-03-23, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1406034, encodeId=dbc61406034bc, content=<a href='/topic/show?id=a5404e589d7' target=_blank style='color:#2F92EE;'>#局部#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=111, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=47589, encryptionId=a5404e589d7, topicName=局部)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=d14c2562456, createdName=chg122, createdTime=Tue Mar 23 05:54:49 CST 2021, time=2021-03-23, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1473517, encodeId=b8ca14e351775, content=<a href='/topic/show?id=4fd1e102257' target=_blank style='color:#2F92EE;'>#病理学#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=121, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=71022, encryptionId=4fd1e102257, topicName=病理学)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=c8ce7226273, createdName=jktdtl, createdTime=Tue Mar 23 05:54:49 CST 2021, time=2021-03-23, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1491398, encodeId=2db8149139863, content=<a href='/topic/show?id=5316e4387aa' target=_blank style='color:#2F92EE;'>#神经病#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=86, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=74387, encryptionId=5316e4387aa, topicName=神经病)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=1ab48885684, createdName=axin012, createdTime=Tue Mar 23 05:54:49 CST 2021, time=2021-03-23, status=1, ipAttribution=)]
    2021-03-23 neurowu
  6. [GetPortalCommentsPageByObjectIdResponse(id=1786448, encodeId=daaa1e86448d2, content=<a href='/topic/show?id=569f13e9045' target=_blank style='color:#2F92EE;'>#Pathol#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=137, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=13790, encryptionId=569f13e9045, topicName=Pathol)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=4b65161, createdName=yb6560, createdTime=Sat Jan 22 01:54:49 CST 2022, time=2022-01-22, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1850109, encodeId=7938185010997, content=<a href='/topic/show?id=61815385aa' target=_blank style='color:#2F92EE;'>#CTA#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=0, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=5385, encryptionId=61815385aa, topicName=CTA)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=ec9955, 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ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1491398, encodeId=2db8149139863, content=<a href='/topic/show?id=5316e4387aa' target=_blank style='color:#2F92EE;'>#神经病#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=86, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=74387, encryptionId=5316e4387aa, topicName=神经病)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=1ab48885684, createdName=axin012, createdTime=Tue Mar 23 05:54:49 CST 2021, time=2021-03-23, status=1, ipAttribution=)]
    2021-03-23 wushaoling
  7. 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    2021-03-23 jktdtl
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    2021-03-23 axin012

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