Early postnatal behavioral, cellular, and molecular changes in models of Huntington disease are reversible by HDAC inhibition.
Early postnatal behavioral, cellular, and molecular changes in models of Huntington disease are reversible by HDAC inhibition.
复制标题
DOI：
10.1073/pnas.1807962115
复制
发表时间：
2018-09-11
影响因子：
11.1
通讯作者：
von Hörsten S
中科院分区：
文献类型：
--
作者：
Siebzehnrübl FA;Raber KA;Urbach YK;Schulze-Krebs A;Canneva F;Moceri S;Habermeyer J;Achoui D;Gupta B;Steindler DA;Stephan M;Nguyen HP;Bonin M;Riess O;Bauer A;Aigner L;Couillard-Despres S;Paucar MA;Svenningsson P;Osmand A;Andreew A;Zabel C;Weiss A;Kuhn R;Moussaoui S;Blockx I;Van der Linden A;Cheong RY;Roybon L;Petersén Å;von Hörsten S
在亨廷顿病(HD)基因携带者中，致病突变Huntingtin(MHTT)在早期发育阶段就已经存在，但令人惊讶的是，HD患者在许多年后才出现临床症状。虽然亨廷顿的发育作用已经被描述，但到目前为止，还缺乏针对这些早期神经发育过程的新的治疗方法。在这里，我们表明，在遗传性HD动物模型的出生后阶段，与mHTT相关的行为、细胞和分子变化可以通过使用组蛋白去乙酰化抑制剂的低剂量治疗来逆转。我们的发现支持HD的神经发育基础，并提供了HD前症状，包括异常的神经元分化，通过体内早期治疗干预是可逆的概念证据。亨廷顿病(HD)是一种常染色体显性遗传性神经退行性疾病，由亨廷顿蛋白基因(HTT)中CAG重复序列扩大引起。虽然突变的HTT在胚胎发育和整个生命过程中都有表达，但临床HD通常在成年后表现出来。许多研究记录了与突变HTT相关的神经发育变化，但这些变化在治疗下是否可逆仍不清楚。在这里，我们确定了断奶前转基因HD大鼠和小鼠的非常早期的行为、分子和细胞变化。伴随着体内多巴胺能调节紊乱、室下区干细胞/祖细胞的神经元分化能力降低以及体外小鼠胚胎神经干细胞的神经元和少突胶质细胞分化的损害，超声发声减弱、脉冲前抑制的丧失和冒险行为的增加。用组蛋白脱乙酰酶抑制剂(HDACi)LBH589介入治疗这种早期表型可以显著改善行为改变和多巴胺能神经传递的标志物，并在体外和体内完全逆转异常神经元的分化。我们的数据支持这一观点，即神经发育变化有助于HD的前驱阶段，使用HDACi的早期症状前干预可能是HD的一种有前途的新治疗方法。
In Huntington disease (HD) gene carriers the disease-causing mutant Huntingtin (mHTT) is already present during early developmental stages, but, surprisingly, HD patients develop clinical symptoms only many years later. While a developmental role of Huntingtin has been described, so far new therapeutic approaches targeting those early neurodevelopmental processes are lacking. Here, we show that behavioral, cellular, and molecular changes associated with mHTT in the postnatal period of genetic animal models of HD can be reverted using low-dose treatment with a histone deacetylation inhibitor. Our findings support a neurodevelopmental basis for HD and provide proof of concept that pre-HD symptoms, including aberrant neuronal differentiation, are reversible by early therapeutic intervention in vivo. Huntington disease (HD) is an autosomal dominant neurodegenerative disorder caused by expanded CAG repeats in the huntingtin gene (HTT). Although mutant HTT is expressed during embryonic development and throughout life, clinical HD usually manifests later in adulthood. A number of studies document neurodevelopmental changes associated with mutant HTT, but whether these are reversible under therapy remains unclear. Here, we identify very early behavioral, molecular, and cellular changes in preweaning transgenic HD rats and mice. Reduced ultrasonic vocalization, loss of prepulse inhibition, and increased risk taking are accompanied by disturbances of dopaminergic regulation in vivo, reduced neuronal differentiation capacity in subventricular zone stem/progenitor cells, and impaired neuronal and oligodendrocyte differentiation of mouse embryo-derived neural stem cells in vitro. Interventional treatment of this early phenotype with the histone deacetylase inhibitor (HDACi) LBH589 led to significant improvement in behavioral changes and markers of dopaminergic neurotransmission and complete reversal of aberrant neuronal differentiation in vitro and in vivo. Our data support the notion that neurodevelopmental changes contribute to the prodromal phase of HD and that early, presymptomatic intervention using HDACi may represent a promising novel treatment approach for HD.
登录
查看更多内容
影响因子：
6.1
作者：
Arteaga-Bracho, Eduardo E.;Gulinello, Maria;Winchester, Michael L.;Pichamoorthy, Nandini;Petronglo, Jenna R.;Zambrano, Alicia D.;Inocencio, Julio;De Jesus, Chirstopher D.;Louie, Joseph O.;Gokhan, Solen;Mehler, Mark F.;Molero, Aldrin E.
通讯作者：
Molero, Aldrin E.
DOI：
10.3233/jhd-160226
发表时间：
2016-12-15
期刊：
Journal of Huntington's disease
影响因子：
--
作者：
Chopra V;Quinti L;Khanna P;Paganetti P;Kuhn R;Young AB;Kazantsev AG;Hersch S
通讯作者：
Hersch S
影响因子：
2.5
作者：
Brown, JP;Couillard-Després, S;Kuhn, HG
通讯作者：
Kuhn, HG
影响因子：
30.8
作者：
ANDREW, SE;GOLDBERG, YP;HAYDEN, MR
通讯作者：
HAYDEN, MR
影响因子：
3.5
作者：
Bode, Felix J.;Stephan, Michael;von Hoersten, Stephan
通讯作者：
von Hoersten, Stephan