Gozutok Oge, Helmold Benjamin Ryan, Ozdinler P Hande
Department of Neurology, Feinberg School of Medicine, Northwestern University, 303 E. Chicago Ave, Chicago, IL 60611, USA.
Center for Molecular Innovation and Drug Discovery, Center for Developmental Therapeutics, Chemistry of Life Processes Institute, Northwestern University, Evanston, IL 60611, USA.
Brain Sci. 2021 Apr 29;11(5):578. doi: 10.3390/brainsci11050578.
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.
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（UMNs）。UMNs表现出早期易损性和进行性退化，而其他皮质神经元大多仍保持功能。对众多直接与HSP和PLS相关或与之关联的突变的鉴定，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鉴定出来的，而且细胞功能大多依赖于蛋白质-蛋白质相互作用，我们推测在患者中检测到的突变以及蛋白质相互作用结构域的改变将是揭示其易损性根本原因的关键。为了获得机制上的见解，我们利用计算分析来鉴定蛋白质的相互作用伙伴，并绘制了关于HSP和PLS的蛋白质-蛋白质相互作用图谱。蛋白质-蛋白质相互作用结构域、上游调节因子和经典途径开始凸显关键的细胞事件。在此我们报告，参与维持脂质稳态和细胞结构动力学的蛋白质及其相互作用对UMN的健康和稳定性至关重要。它们的扰动可能导致神经元易损性，因此维持它们的平衡可能提供治疗干预措施。
