Laboratory of Genetics, Department of Biotechnology, School of Applied Biology and Biotechnology, Agricultural University of Athens, 75 Iera Odos, 11855 Athens, Greece.
Department of Biomedical Sciences, School of Health and Care Sciences, University of West Attica, Agioy Spyridonos, 12243 Egaleo, Greece.
Genes (Basel). 2024 Apr 23;15(5):529. doi: 10.3390/genes15050529.
The evolutionary conserved Notch signaling pathway functions as a mediator of direct cell-cell communication between neighboring cells during development. Notch plays a crucial role in various fundamental biological processes in a wide range of tissues. Accordingly, the aberrant signaling of this pathway underlies multiple genetic pathologies such as developmental syndromes, congenital disorders, neurodegenerative diseases, and cancer. Over the last two decades, significant data have shown that the Notch signaling pathway displays a significant function in the mature brains of vertebrates and invertebrates beyond neuronal development and specification during embryonic development. Neuronal connection, synaptic plasticity, learning, and memory appear to be regulated by this pathway. Specific mutations in human Notch family proteins have been linked to several neurodegenerative diseases including Alzheimer's disease, CADASIL, and ischemic injury. Neurodegenerative diseases are incurable disorders of the central nervous system that cause the progressive degeneration and/or death of brain nerve cells, affecting both mental function and movement (ataxia). There is currently a lot of study being conducted to better understand the molecular mechanisms by which Notch plays an essential role in the mature brain. In this study, an in silico analysis of polymorphisms and mutations in human Notch family members that lead to neurodegenerative diseases was performed in order to investigate the correlations among Notch family proteins and neurodegenerative diseases. Particular emphasis was placed on the study of mutations in the Notch3 protein and the structure analysis of the mutant Notch3 protein that leads to the manifestation of the CADASIL syndrome in order to spot possible conserved mutations and interpret the effect of these mutations in the Notch3 protein structure. Conserved mutations of cysteine residues may be candidate pharmacological targets for the potential therapy of CADASIL syndrome.
进化保守的 Notch 信号通路在发育过程中作为相邻细胞之间直接细胞间通讯的介质起作用。 Notch 在广泛的组织中多种基本生物学过程中发挥着关键作用。因此，该途径的异常信号转导是多种遗传病理学的基础，如发育综合征、先天性疾病、神经退行性疾病和癌症。在过去的二十年中，大量数据表明 Notch 信号通路在脊椎动物和无脊椎动物的成熟脑中具有重要功能，超出了胚胎发育过程中神经元发育和特化的范围。神经元连接、突触可塑性、学习和记忆似乎受该途径调节。人类 Notch 家族蛋白中的特定突变与几种神经退行性疾病有关，包括阿尔茨海默病、CADASIL 和缺血性损伤。神经退行性疾病是中枢神经系统不可治愈的疾病，导致脑神经元进行性退化和/或死亡，影响精神功能和运动（共济失调）。目前正在进行大量研究，以更好地了解 Notch 在成熟脑中发挥重要作用的分子机制。在这项研究中，对导致神经退行性疾病的人类 Notch 家族成员的多态性和突变进行了计算机分析，以研究 Notch 家族蛋白与神经退行性疾病之间的相关性。特别强调了 Notch3 蛋白突变的研究和导致 CADASIL 综合征的突变 Notch3 蛋白的结构分析，以发现可能的保守突变，并解释这些突变对 Notch3 蛋白结构的影响。半胱氨酸残基的保守突变可能是 CADASIL 综合征潜在治疗的候选药物靶点。
