Neurodegenerative Diseases: A New Class of Primary Developmental Disorders?

神经退行性疾病的发病机制尚不清楚。衰老大脑的这些不同疾病的标志是，在这些长寿的神经元亚型诞生几十年后，在疾病特定模式下的选择性细胞脆弱性。研究病理性脑衰老和神经退行性变的标准范式传统上侧重于定义在成人生活中介导神经元功能障碍和死亡的生物学过程和途径，并将这些疾病视为离散的病理实体，而不是最终共同致病过程的连续体。与标准范式相反，我们假设神经退行性疾病代表了一类新的神经发育基础疾病，其中干细胞介导的神经发生区域程序中的细微损伤导致选择性神经元和神经网络对一系列晚年压力源的脆弱性。与我们的假设一致，我们对亨廷顿氏病和阿尔茨海默病小鼠敲入模型中发育性干细胞介导的损伤的互补特征的初步观察支持了在出生异常和易感神经元亚型死亡之间存在精子致病性关联的可能性。因此，我们的具体目标是在一个特征明确的疾病模型中，建立早期发育障碍与迟发性神经退行性过程的临床、病理和神经生理标志之间的因果关系。作为概念的证明，我们将采用亨廷顿氏病小鼠模型，通过在发育前后切除或诱导突变基因的表达，并评估基因操作对选择性细胞易感性、功能障碍和神经变性特征特征的进化的影响，来确定早期发育障碍是否与该疾病直接相关。验证我们的假设将提供令人信服的实验证据，证明亨廷顿氏病可能代表了一种基本的新型发育障碍，对理解其他神经退行性疾病的发病机制具有直接意义。实现这一非常规假设的目标将解决生物医学科学中最令人烦恼的概念问题之一，该问题阻碍了该领域早期诊断、治疗和预防的进展：神经退行性疾病中不变的区域细胞脆弱性的潜在原因是什么？这一建议特别适合于EUREKA机制，因为它在解决一个特别困难的生物医学问题方面具有新奇的概念，具有极其广泛的科学和公共卫生相关性。此外，非传统的关注发展机制介导的衰老的大脑疾病和影响多器官系统的相关合并症将创造重要的新的跨学科协同效应，与多个NIH研究所的目标密切相关。

The pathogenesis of neurodegenerative diseases remains obscure. The hallmark of these diverse disorders of the aging brain is selective cell vulnerability in disease-specific patterns many decades after the birth of these long-lived neuronal subtypes. The standard paradigm for investigating pathological brain aging and neurodegeneration has traditionally focused on defining the biological processes and pathways mediating neuronal dysfunction and death during adult life and has considered these disorders as discrete pathological entities rather than as a continuum of a final common pathogenic process. In contrast to the standard paradigm, we hypothesize that neurodegenerative diseases represent a novel class of fundamental disorders of neural development in which subtle impairments in the regional program of stem cell-mediated neurogenesis create selective neuronal and neural network vulnerabilities to a spectrum of late-life stressors. Consistent with our hypothesis, our preliminary observations of complementary profiles of developmental stem cell-mediated impairments in mouse knock-in models of Huntington's and Alzheimer's diseases support the possibility of seminal pathogenic associations between abnormalities in the birth and the death of the vulnerable neuronal subtypes. Therefore, our Specific Aim is to establish causal links between the early developmental impairments and the occurrence of the clinical, pathologic and neurophysiologic hallmarks of the late- onset neurodegenerative process in a well-characterized disease model. As a proof of concept, we will employ Huntington's disease mouse models to determine whether the early developmental impairments are directly responsible for the disease by ablating or inducing expression of the mutant gene both before and after development and assessing the consequences of the gene manipulations for evolution of the characteristic profiles of selective cell vulnerability, dysfunction and neurodegeneration. Verification of our hypothesis will provide compelling experimental evidence that Huntington's disease may represent a fundamental new class of developmental disorders with direct implications for understanding the pathogenesis of other neurodegenerative diseases. Fulfilling the objectives of this unconventional hypothesis would address one of the most vexing conceptual problems in the biomedical sciences that have prevented progress in early diagnosis, treatment and prevention within this field: what is the underlying cause of the invariant regional cellular vulnerabilities in neurodegenerative diseases. This proposal is particularly well suited to the EUREKA mechanism because of its conceptual novelty in addressing a particularly difficult biomedical problem of exceptionally broad scientific as well as public health relevance. Moreover, the unconventional focus on developmental mechanisms mediating diseases of the aging brain and associated co-morbidities affecting multiple organ systems will create important new cross-disciplinary synergies germane to the objectives of multiple NIH Institutes.