PDF(Pubmed)
Abstract：
Huntington\'s disease (HD) is a monogenic disease that results in a combination of motor, psychiatric, and cognitive symptoms. It is caused by a CAG trinucleotide repeat expansion in the exon 1 of the huntingtin (HTT) gene, which results in the production of a mutant HTT protein (mHTT) with an extended polyglutamine tract (PolyQ). Severe motor symptoms are a hallmark of HD and typically appear during middle age; however, mild cognitive and personality changes often occur already during early adolescence. Wild-type HTT is a regulator of synaptic functions and plays a role in axon guidance, neurotransmitter release, and synaptic vesicle trafficking. These functions are important for proper synapse assembly during neuronal network formation. In the present study, we assessed the effect of mHTT exon1 isoform on the synaptic and functional maturation of human induced pluripotent stem cell (hiPSC)-derived neurons. We used a relatively fast-maturing hiPSC line carrying a doxycycline-inducible pro-neuronal transcription factor, (iNGN2), and generated a double transgenic line by introducing only the exon 1 of HTT, which carries the mutant CAG (mHTTEx1). The characterization of our cell lines revealed that the presence of mHTTEx1 in hiPSC-derived neurons alters the synaptic protein appearance, decreases synaptic contacts, and causes a delay in the development of a mature neuronal activity pattern, recapitulating some of the developmental alterations observed in HD models, nonetheless in a shorted time window. Our data support the notion that HD has a neurodevelopmental component and is not solely a degenerative disease.
摘要：
亨廷顿病（HD）是一种单基因疾病，导致运动，精神病学,和认知症状。它是由亨廷顿（HTT）基因外显子1中的CAG三核苷酸重复扩增引起的，这导致产生具有延伸的聚谷氨酰胺束(PolyQ)的突变HTT蛋白(mHTT)。严重的运动症状是HD的标志，通常出现在中年时期;然而，轻度的认知和人格变化往往已经发生在青春期早期。野生型HTT是突触功能的调节因子，在轴突导向中起作用，神经递质释放，和突触小泡贩运。这些功能对于神经元网络形成过程中的正确突触组装很重要。在本研究中,我们评估了mHTT外显子1同工型对人诱导多能干细胞（hiPSC）衍生神经元的突触和功能成熟的影响。我们使用了一个相对快速成熟的hiPSC细胞系，携带多西环素诱导的神经元前转录因子，(iNGN2),并通过仅引入HTT的外显子1产生了双转基因系，其携带突变CAG(mHTTEx1)。我们细胞系的表征表明，hiPSC衍生神经元中mHTTEx1的存在改变了突触蛋白的外观，减少突触接触，并导致成熟神经元活动模式的发育延迟，概括了在HD模型中观察到的一些发育改变，在一个短暂的时间窗口。我们的数据支持以下观点：HD具有神经发育成分，而不仅仅是一种退行性疾病。
