The Neurodevelopmental Hypothesis of Huntington's Disease.
The Neurodevelopmental Hypothesis of Huntington's Disease.
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DOI：
10.3233/jhd-200394
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Nopoulos PC
中科院分区：
文献类型：
--
作者：
van der Plas E;Schultz JL;Nopoulos PC
HD病因学的当前教条假定它是一种主要影响纹状体的退行性疾病，由杀死神经元的突变mHTT的功能获得（毒性）引起。然而，越来越多的证据支持另一种理论，即功能丧失也可能影响病理学，这一理论的基础是HTT是大脑发育的重要基因。mHTT在整个生命中表达，并且可以想象对大脑发育具有有害影响。当然，这种疾病的最终结果是神经退行性变;然而，发生这种情况的过程可能植根于异常发育的病理生理学。迄今为止，已有多项研究评估了HD异常发育的分子和细胞机制，以及研究了HD动物模型中的异常脑发育。然而，关于mHTT如何影响人类神经发育的直接研究直到最近几年才开始。目前的审查将集中在一个独特的研究儿童在HD的风险，儿童HD研究的最新结果。这项研究评估了6-18岁有HD风险的儿童（父母或祖父母患有HD）的大脑结构和功能。
The current dogma of HD pathoetiology posits it is a degenerative disease affecting primarily the striatum, caused by a gain of function (toxicity) of the mutant mHTT that kills neurons. However, a growing body of evidence supports an alternative theory in which loss of function may also influence the pathology.This theory is predicated on the notion that HTT is known to be a vital gene for brain development. mHTT is expressed throughout life and could conceivably have deleterious effects on brain development. The end event in the disease is, of course, neurodegeneration; however the process by which that occurs may be rooted in the pathophysiology of aberrant development. To date, there have been multiple studies evaluating molecular and cellular mechanisms of abnormal development in HD, as well as studies investigating abnormal brain development in HD animal models. However, direct study of how mHTT could affect neurodevelopment in humans has not been approached until recent years. The current review will focus on the most recent findings of a unique study of children at-risk for HD, the Kids-HD study. This study evaluates brain structure and function in children ages 6–18 years old who are at risk for HD (have a parent or grand-parent with HD).