Dinamarca Margarita C, Colombo Laura, Tousiaki Natalia E, Müller Matthias, Pecho-Vrieseling Eline
Department of Biomedicine, University of Basel, Basel, Switzerland.
Novartis Institute for Biomedical Research, Basel, Switzerland.
Front Mol Biosci. 2022 Jul 19;9:916019. doi: 10.3389/fmolb.2022.916019. eCollection 2022.
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 () 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 which carries the mutant CAG (). 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.
亨廷顿舞蹈症（HD）是一种单基因疾病，会导致运动、精神和认知症状的综合表现。它由亨廷顿蛋白（HTT）基因外显子1中的CAG三核苷酸重复序列扩增引起，这会导致产生一种具有延长的多聚谷氨酰胺链（PolyQ）的突变型HTT蛋白（mHTT）。严重的运动症状是HD的一个标志，通常在中年出现；然而，轻度的认知和性格变化在青春期早期就经常会发生。野生型HTT是突触功能的调节因子，在轴突导向、神经递质释放和突触小泡运输中发挥作用。这些功能对于神经网络形成过程中正确的突触组装很重要。在本研究中，我们评估了mHTT外显子1亚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。我们使用了一种携带强力霉素诱导型神经前体细胞转录因子（iNGN2）的相对快速成熟的hiPSC系，并通过仅引入携带突变CAG的HTT外显子1来生成双转基因系。我们细胞系的特征表明，hiPSC衍生神经元中mHTTEx1的存在会改变突触蛋白的出现，减少突触接触，并导致成熟神经元活动模式的发育延迟，重现了在HD模型中观察到的一些发育改变，尽管是在更短的时间范围内。我们的数据支持这样一种观点，即HD具有神经发育成分，而不仅仅是一种退行性疾病。
