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Abstract：
Hereditary spastic paraplegia (HSP) and primary lateral sclerosis (PLS) are rare motor neuron diseases, which affect mostly the upper motor neurons (UMNs) in patients. The UMNs display early vulnerability and progressive degeneration, while other cortical neurons mostly remain functional. Identification of numerous mutations either directly linked or associated with HSP and PLS begins to reveal the genetic component of UMN diseases. Since each of these mutations are identified on genes that code for a protein, and because cellular functions mostly depend on protein-protein interactions, we hypothesized that the mutations detected in patients and the alterations in protein interaction domains would hold the key to unravel the underlying causes of their vulnerability. In an effort to bring a mechanistic insight, we utilized computational analyses to identify interaction partners of proteins and developed the protein-protein interaction landscape with respect to HSP and PLS. Protein-protein interaction domains, upstream regulators and canonical pathways begin to highlight key cellular events. Here we report that proteins involved in maintaining lipid homeostasis and cytoarchitectural dynamics and their interactions are of great importance for UMN health and stability. Their perturbation may result in neuronal vulnerability, and thus maintaining their balance could offer therapeutic interventions.
摘要：
遗传性痉挛性截瘫（HSP）和原发性侧索硬化症（PLS）是罕见的运动神经元疾病，主要影响患者的上运动神经元(UMN)。UMN表现出早期的脆弱性和进行性退化，而其他皮质神经元大多保持功能。与HSP和PLS直接相关或相关的许多突变的鉴定开始揭示UMN疾病的遗传成分。由于这些突变中的每一个都是在编码蛋白质的基因上发现的，因为细胞功能主要取决于蛋白质-蛋白质相互作用，我们假设在患者中检测到的突变和蛋白质相互作用域的改变将是揭示其脆弱性的根本原因的关键.为了带来机械的洞察力，我们利用计算分析来确定蛋白质的相互作用伙伴,并开发了关于HSP和PLS的蛋白质-蛋白质相互作用格局.蛋白质-蛋白质相互作用域，上游调节因子和典型通路开始突出关键细胞事件。在这里，我们报道了维持脂质稳态和细胞结构动力学及其相互作用的蛋白质对于UMN的健康和稳定性非常重要。它们的扰动可能导致神经元脆弱，因此，保持它们的平衡可以提供治疗干预。
