Mehler M F, Gokhan S
Laboratory of Developmental and Molecular Neuroscience, Department of Neurology, Rose F. Kennedy Center for Research in Mental Retardation and Developmental Disabilities, Albert Einstein College of Medicine, Bronx 10461, NY, USA.
Prog Neurobiol. 2001 Feb;63(3):337-63. doi: 10.1016/s0301-0082(00)00052-6.
Cellular genes that are mutated in neurodegenerative diseases code for proteins that are expressed throughout neural development. Genetic analysis suggests that these genes are essential for a broad range of normal neurodevelopmental processes. The proteins they code for interact with numerous other cellular proteins that are components of signaling pathways involved in patterning of the neural tube and in regional specification of neuronal subtypes. Further, pathogenetic mutations of these genes can cause progressive, sublethal alterations in the cellular homeostasis of evolving regional neuronal subpopulations, culminating in late-onset cell death. Therefore, as a consequence of the disease mutations, targeted cell populations may retain molecular traces of abnormal interactions with disease-associated proteins by exhibiting changes in a spectrum of normal cellular functions and enhanced vulnerability to a host of environmental stressors. These observations suggest that the normal functions of these disease-associated proteins are to ensure the fidelity and integration of developmental events associated with the progressive elaboration of neuronal subtypes as well as the maintenance of mature neuronal populations during adult life. The ability to identify alterations within vulnerable neuronal precursors present in pre-symptomatic individuals prior to the onset of irrevocable cellular injury may help foster the development of effective therapeutic interventions using evolving pharmacologic, gene and stem cell technologies.
在神经退行性疾病中发生突变的细胞基因编码在整个神经发育过程中表达的蛋白质。遗传分析表明，这些基因对于广泛的正常神经发育过程至关重要。它们编码的蛋白质与许多其他细胞蛋白质相互作用，这些蛋白质是参与神经管模式形成和神经元亚型区域特化的信号通路的组成部分。此外，这些基因的致病突变可导致不断演变的区域神经元亚群的细胞内稳态发生渐进性、亚致死性改变，最终导致迟发性细胞死亡。因此，作为疾病突变的结果，靶向细胞群体可能通过表现出一系列正常细胞功能的变化以及对多种环境应激源的易感性增加，而保留与疾病相关蛋白质异常相互作用的分子痕迹。这些观察结果表明，这些疾病相关蛋白质的正常功能是确保与神经元亚型逐步细化相关的发育事件的保真度和整合，以及在成年期维持成熟神经元群体。在不可逆转的细胞损伤发生之前，识别出无症状个体中存在的易损神经元前体细胞内的变化，这一能力可能有助于利用不断发展的药理学、基因和干细胞技术推动有效治疗干预措施的开发。
