Huntington's disease: a novel developmental oligodendrogliopathy

亨廷顿病：一种新型的发育性少突胶质细胞病

• 批准号: 9233213
• 负责人: Mark F Mehler
• 金额: $ 36.53万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE, INC
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-01 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9233213
• 关键词: Ablation; Address; Adult; Alzheimer' s Disease; Architecture; Biological Markers; Cells; Ceroid; Characteristics; Chronic; Cognitive; Complement; Corpus striatum structure; Data; Defect; Demyelinations; Dentatorubral-Pallidoluysian Atrophies; Development; Disease; Disease Outcome; Disease Progression; Dorsal; Exhibits; Functional disorder; Ganglia; Genes; Genetic; Goals; Gray unit of radiation dose; Human; Huntington Disease; Huntington gene; Impaired cognition; Impairment; Intervention; Knock-in; Knock-in Mouse; Lateral; Lead; Life; Medial; Mediating; Modeling; Molecular; Molecular Genetics; Motor; Multiple System Atrophy; Myelin; Nature; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Oligodendroglia; Onset of illness; Outcome; Parkinson Disease; Pathogenesis; Pathogenicity; Pathologic; Pathology; Phase; Phenotype; Play; Prosencephalon; Replacement Therapy; Reporter; Research; Role; Secondary to; Specimen; Supporting Cell; Testing; Therapeutic; Therapeutic Intervention; Therapeutic Studies; Transplantation; White Matter Disease; Work; base; disability; genetic manipulation; innovation; insight; motor deficit; mouse model; mutant; myelination; nervous system disorder; neurodevelopment; neuron loss; neuropsychiatry; new therapeutic target; novel; oligodendrocyte lineage; oligodendrocyte precursor; postnatal; prevent; programs; public health relevance; relating to nervous system; selective expression; stem; targeted treatment; time use; white matter

 DESCRIPTION (provided by applicant): Huntington's disease: a novel developmental oligodendrogliopathy Huntington's disease (HD) is a relentlessly progressive neurodegenerative disorder that typically presents with progressive cognitive/motor deficits. Although HD exhibits a unitary genetic basis (mutant huntingtin [mHtt]), our understanding of HD pathogenesis remains poorly defined. The hallmark of HD is degeneration of striatal medium spiny neurons (MSNs). Therefore, study of HD has focused predominantly on cell autonomous mechanisms mediating MSN death. However, there is increasing recognition that HD pathology also encompasses dysfunction of oligodendrocytes (OLs), myelin and white matter tracts (WMTs). These defects occur during prodromal phases of HD, suggesting that non-cell autonomous mechanisms mediated by OLs may play important roles in HD pathogenesis. Here, we test the hypothesis that postnatal WMT abnormalities are: (1) secondary to defects in the second wave of developmental forebrain oligodendrogliogenesis leading to ectopic persistence of non-myelinating OLs from the first wave, and (2) necessary for region-specific profiles of forebrain vulnerability to neurodegeneration. This developmental hypothesis is based on our experimental data showing: (1) impairments in multiple NSC-mediated MSN developmental parameters in a HD knock-in mouse model, (2) early and stable OL impairments in HD mouse models/human pathological specimens, (3) key conjoint roles of Gsx2 in mediating MSN and OL second wave developmental functions, and (4) selective temporal ablation of mHtt after neural development recapitulates characteristic features of HD (EUREKA R01). Our Specific Aims are to define: (1) roles of ventrally- vs. dorsally-derived developmental OLs in HD WMT abnormalities, (2) pathogenic roles of OLs and WMT abnormalities in HD pathogenesis and therapeutic benefits of OL-based molecular genetic and cell replacement interventions. Our research approach will study: (I) differential ontogenic expression of Gsx2 in HD, (II) dynamic OL-specific lineage aberrations in HD, (III) molecular genetic rescue of Gsx2-dependent OL deficits in HD, (IV) role of HD-associated OL abnormalities in HD pathogenesis via conditional ablation of mHtt in OL precursors, (V) effects on HD onset/progression of OL cell replacement strategies. The Significance includes: (A) defining the developmental nature of HD OL lineage abnormalities, (B) establishing that a non-neuronal/non-cell autonomous mechanism is part of the pathogenic cascade leading to neuronal cell death, (C) establishing that HD represents a new class of primary developmental oligodendrogliopathy, (D) initiating entirely new directions for gene and cell based therapeutic studies during the prodromal phase based upon the HD-mediated OL developmental dysfunction. The Innovation is (1) proposing a novel mechanism underlying HD pathogenesis by incorporating a "two-hit" model including developmental forebrain OL deficits, (2) employing OL lineage-tracing to study the HD developmental oligodendrogliopathy, (3) using time-specific conditional genetic manipulations to rescue the putative HD developmental oligodendrogliopathy, (4) using cell replacement of OL developmental species to treat HD.

 描述（由申请人提供）：亨廷顿病：一种新型发育性少突胶质细胞病亨廷顿病（HD）是一种持续进行性神经退行性疾病，通常表现为进行性认知/运动缺陷。虽然HD表现出单一的遗传基础（突变亨廷顿蛋白[mHtt]），我们对HD发病机制的理解仍然不清楚。HD的标志是纹状体中棘神经元（MSN）的变性。因此，HD的研究主要集中在介导MSN死亡的细胞自主机制上。然而，越来越多的人认识到HD病理学还包括少突胶质细胞（OL）、髓鞘和白色物质束（WMT）的功能障碍。这些缺陷发生在前驱期的HD，这表明非细胞自主机制介导的OL可能在HD的发病机制中发挥重要作用。在这里，我们测试的假设，出生后WMT异常：（1）继发于缺陷的第二波发育前脑少突胶质细胞导致异位持久性的非髓鞘化OL从第一波，和（2）必要的前脑脆弱性神经变性的区域特异性配置文件。这一发展假说是基于我们的实验数据显示：（1）在HD敲入小鼠模型中多个NSC介导的MSN发育参数的损伤，（2）在HD小鼠模型/人类病理标本中早期和稳定的OL损伤，（3）Gsx 2在介导MSN和OL第二波发育功能中的关键联合作用，（4）在神经发育后选择性地暂时消融mHtt，重现了HD的特征（尤里卡R 01）。我们的具体目标是定义：（1）腹侧与背侧发育OL在HD WMT异常中的作用，（2）OL和WMT异常在HD发病机制中的致病作用以及基于OL的分子遗传和细胞替代干预的治疗益处。我们的研究方法将研究：（I）HD中Gsx 2的差异个体发育性表达，（II）HD中动态OL特异性谱系畸变，（III）HD中Gsx 2依赖性OL缺陷的分子遗传拯救，（IV）通过条件性消融OL前体中的mHtt，HD相关OL异常在HD发病机制中的作用，（V）OL细胞替代策略对HD发作/进展的影响。其意义包括：（A）定义HD OL谱系异常的发育性质，（B）确定非神经元/非细胞自主机制是导致神经元细胞死亡的致病级联的一部分，（C）确定HD代表一类新的原发性发育性少突胶质细胞病，（D）在前驱期期间基于HD启动基于基因和细胞的治疗研究的全新方向-介导的OL发育障碍。该创新是（1）通过纳入包括发育性前脑OL缺陷的“两次打击”模型，提出了HD发病机制的新机制，（2）采用OL谱系追踪研究HD发育性少突胶质细胞病，（3）使用时间特异性条件性遗传操作挽救推定的HD发育性少突胶质细胞病，（4）使用OL发育物种的细胞替代治疗HD。