How CTIP2 deficiency drives medium spiny neuron degeneration and dysfunction: implications in Huntington's disease pathogenesis

亨廷顿病(HD)是一种在老龄化社会中日益流行并逐渐致残的痴呆症。这种神经退行性疾病是由亨廷顿基因中的胞嘧啶-腺嘌呤-鸟嘌呤(CAG)三核苷酸扩张引起的。除运动障碍外，HD还以严重痴呆症为特征，包括情绪和思维能力受损，以及严重的记忆力丧失，足以干扰日常生活。HD对患者及其家人的影响及其对卫生保健系统的负担正在呈指数级增长。目前还没有治愈或改善疾病的治疗方法来延缓这种疾病的发生和发展。纹状体变性，特别是中棘神经元(MSN)的丢失，是HD的标志性病理。尽管使用转基因动物和患者来源的人类诱导多能干细胞(HiPSCs)建立疾病模型的研究取得了进展，但人们对这种选择性HD病理的确切机制知之甚少，这种病理机制阻碍了适当和有效的治疗方法的设计。最近的研究，包括我们自己的初步数据，表明纹状体转录因子Coup TF1相互作用蛋白2(CTIP2)在HD神经变性的特异性中起着重要作用。根据这些发现，我们建议进一步证明CTIP2缺乏导致人类MSN的发病，并确定这一机制在HD发病中的作用程度。了解MSN神经元功能维持的控制对于表征和逆转疾病表型至关重要。在这个项目中，我们将从人类胚胎干细胞(HESCs)中分离出纹状体神经元，使其携带功能障碍的CTIP2，并使健康对照hESCs表达正常的CTIP2。我们将详细研究CTIP2功能障碍引起的细胞病理，并研究其潜在的分子机制。此外，我们将确定CTIP2引起的纹状体神经元缺陷与HD的发病机制有关。相信这些发现将有助于确定治疗干预的新靶点，从而可能提供改变HD进展的手段。

Huntington's disease (HD) is an increasingly prevalent and progressively disabling type of dementia in our ageing society. This neurodegenerative disorder is caused by a cytosine-adenine-guanine (CAG) trinucleotide expansion in the Huntingtin gene. Apart from being a movement disorder, HD is also characterised by severe dementia including impairment of mood and thinking skills and a loss of memory severe enough to interfere with daily life. The impact of HD on patients and their families as well as its burden on health care systems is growing exponentially. Currently there is no cure or disease modifying treatment to delay the onset and progression of this disorder. Striatal degeneration, specifically loss of medium spiny neurons (MSNs), is hallmark pathology of HD. Despite advances in disease modelling using genetically modified animals and patient-derived human induced pluripotent stem cells (hiPSCs), little is known about the precise mechanism underlying this selective HD pathology which impedes design of appropriate and effective therapies. Recent studies, including pilot data of our own, suggest that a striatal transcription factor COUP TF1-interacting protein 2 (CTIP2) plays an important role in the specificity of neurodegeneration in HD. In light of these findings, we propose to further demonstrate that CTIP2 deficiency induces human MSN pathogenesis, and to establish the extent of this mechanism contribute to HD pathogenesis. Understanding the control of MSN neuron functional maintenance is of paramount importance in order to characterise and reverse disease phenotypes.In this project, we will make striatal neurons from human embryonic stem cells (hESCs) engineered to carry a dysfunctional form of CTIP2 and healthy control hESCs expressing normal CTIP2. We will investigate in detail the cellular pathology caused by CTIP2 dysfunction and workout the underlying molecular mechanisms. Moreover, we will establish that striatal neuronal deficits caused by CTIP2 contribute to HD pathogenesis. It is believed that these findings will help to identify novel targets for therapeutic interventions that may provide means to modify HD progression.