Huntington's disease: a novel developmental oligodendrogliopathy

 描述(申请人提供)：亨廷顿病：一种新的发育性少突胶质细胞病亨廷顿病(HD)是一种坚持不懈的进行性神经退行性疾病，典型表现为进行性认知/运动障碍。虽然HD表现出单一的遗传基础(突变的Huntingtin[mHTT])，但我们对HD发病机制的了解仍不明确。HD的特点是纹状体中棘神经元(MSN)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，人们越来越认识到HD病理也包括少突胶质细胞(OL)、髓鞘和白质束(WMT)的功能障碍。这些缺陷发生在HD的前驱期，提示OL介导的非细胞自主机制可能在HD的发病机制中发挥重要作用。在这里，我们检验了一种假设，即出生后WMT异常是：(1)继发于发育前脑少突胶质形成的第二波缺陷，导致从第一波开始的非髓鞘OL的异位持续，以及(2)前脑易患神经变性的区域特异性特征所必需的。这一发育假说基于我们的实验数据，其中包括：(1)多个神经干细胞介导的MSN发育参数在HD小鼠模型中的受损；(2)HD小鼠模型/人类病理标本中早期和稳定的OL损伤；(3)Gsx2在调节MSN和OL第二波发育功能中的关键联合作用；(4)神经发育后选择性消融mHTT概括了HD的特征(Eureka R01)。我们的具体目标是确定：(1)腹侧和背侧发育的OL在HD WMT异常中的作用，(2)OL和WMT异常在HD发病中的致病作用以及基于OL的分子遗传学和细胞替代干预的治疗益处。我们的研究方法将研究：(I)Gsx2在HD中的个体差异表达，(Ii)HD中OL特异的动态谱系异常，(Iii)HD中依赖Gsx2的OL缺陷的分子遗传挽救，(IV)HD相关OL异常在HD发病中的作用，(V)通过有条件地去除OL前体中的mHTT，对HD发病/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代表一类新的原发发育性少突胶质细胞病，(D)基于HD介导的OL发育障碍，在前驱期为基于基因和细胞的治疗研究开辟全新的方向。本文的创新之处在于：(1)提出了一种新的HD发病机制，引入了包括发育性前脑OL缺失的“二次打击”模型；(2)利用OL谱系追踪来研究HD发育性少突胶质病；(3)使用特定时间的条件遗传操作来挽救可能的HD发育性少突胶质病；(4)使用OL发育物种的细胞替换来治疗HD。

 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.