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

CTIP2 缺陷如何导致中型棘神经元变性和功能障碍：对亨廷顿病发病机制的影响

• 批准号: MR/R022429/1
• 负责人: Meng Li
• 金额: $ 90.22万
• 依托单位: CARDIFF UNIVERSITY
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FR022429%2F1
• 关键词: How; CTIP2; deficiency; drives; medium

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.

亨廷顿氏病（HD）是在我们的老龄化社会中日益流行和逐渐致残的痴呆类型。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）三核苷酸扩增引起的。除了是一种运动障碍外，HD的特征还包括严重的痴呆症，包括情绪和思维能力受损以及严重到足以干扰日常生活的记忆丧失。HD对患者及其家庭的影响以及对医疗保健系统的负担呈指数级增长。目前没有治愈或疾病修饰治疗来延迟这种疾病的发作和进展。纹状体变性，特别是中棘神经元（MSN）的损失，是HD的标志性病理学。尽管在使用转基因动物和患者来源的人诱导多能干细胞（hiPSC）的疾病建模方面取得了进展，但对这种选择性HD病理学的确切机制知之甚少，这阻碍了适当和有效疗法的设计。最近的研究，包括我们自己的试点数据，表明纹状体转录因子COUP TF 1相互作用蛋白2（CTIP 2）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CTIP 2缺陷诱导人类MSN发病机制，并建立这种机制有助于HD发病机制的程度。了解MSN神经元功能维持的控制对于预防和逆转疾病表型至关重要。在本项目中，我们将从人胚胎干细胞（hESC）中制备纹状体神经元，这些细胞被工程化以携带功能失调形式的CTIP 2和表达正常CTIP 2的健康对照hESC。我们将详细研究CTIP 2功能障碍引起的细胞病理学，并研究其潜在的分子机制。此外，我们将确定CTIP 2引起的纹状体神经元缺陷有助于HD的发病机制。据信，这些发现将有助于确定治疗干预的新靶点，这些新靶点可能提供改变HD进展的方法。

项目成果

miR-34b/c Regulates Wnt1 and Enhances Mesencephalic Dopaminergic Neuron Differentiation.

• DOI: 10.1016/j.stemcr.2018.02.006
• 发表时间: 2018-04-10
• 期刊: Stem cell reports
• 影响因子: 5.9
• 作者: De Gregorio R;Pulcrano S;De Sanctis C;Volpicelli F;Guatteo E;von Oerthel L;Latagliata EC;Esposito R;Piscitelli RM;Perrone-Capano C;Costa V;Greco D;Puglisi-Allegra S;Smidt MP;di Porzio U;Caiazzo M;Mercuri NB;Li M;Bellenchi GC
• 通讯作者: Bellenchi GC

A Novel LHX6 Reporter Cell Line for Tracking Human iPSC-Derived Cortical Interneurons.

• DOI: 10.3390/cells11050853
• 发表时间: 2022-03-01
• 期刊: Cells
• 影响因子: 6
• 作者: Cruz-Santos M;Cardo LF;Li M
• 通讯作者: Li M

Pluripotent stem cell derived inhibitory interneurons - principles and applications in health and disease.

多能干细胞衍生的抑制性中间神经元 - 健康和疾病中的原理和应用。

• DOI: 10.4103/1673-5374.265547
• 发表时间: 2020
• 期刊: Neural regeneration research
• 影响因子: 6.1
• 作者: Keefe F

Dysfunction of cAMP-Protein Kinase A-Calcium Signaling Axis in Striatal Medium Spiny Neurons: A Role in Schizophrenia and Huntington's Disease Neuropathology.

• DOI: 10.1016/j.bpsgos.2022.03.010
• 发表时间: 2023-07
• 期刊: Biological psychiatry global open science