Khatoon Fatima, Haque Shafiul, Hashem Anwar, Mahmoud Ahmad, Tashkandi Hanaa, Mathkor Darin, Harakeh Steve, Alghamdi Badra, Kumar Vijay
Amity Institute of Neuropsychology and Neurosciences, Amity University, Noida, Uttar Pradesh, India.
Research and Scientific Studies Unit, College of Nursing and Allied Health Sciences, Jazan University, Jazan, Saudi Arabia.
Front Mol Neurosci. 2022 Dec 16;15:1023286. doi: 10.3389/fnmol.2022.1023286. eCollection 2022.
Amyotrophic Lateral Sclerosis (ALS) is a rare progressive and chronic motor neuron degenerative disease for which at present no cure is available. In recent years, multiple genes encode kinases and other causative agents for ALS have been identified. Kinases are enzymes that show pleiotropic nature and regulate different signal transduction processes and pathways. The dysregulation of kinase activity results in dramatic changes in processes and causes many other human diseases including cancers.
In this study, we have adopted a network-based system biology approach to investigate the kinase-based molecular interplay between ALS and other human disorders. A list of 62 ALS-associated-kinases was first identified and then we identified the disease associated with them by scanning multiple disease-gene interaction databases to understand the link between the ALS-associated kinases and other disorders.
An interaction network with 36 kinases and 381 different disorders associated with them was prepared, which represents the complexity and the comorbidity associated with the kinases. Further, we have identified 5 miRNAs targeting the majority of the kinases in the disease-causing network. The gene ontology and pathways enrichment analysis of those miRNAs were performed to understand their biological and molecular functions along with to identify the important pathways. We also identified 3 drug molecules that can perturb the disease-causing network by drug repurposing.
This network-based study presented hereby contributes to a better knowledge of the molecular underpinning of comorbidities associated with the kinases associated with the ALS disease and provides the potential therapeutic targets to disrupt the highly complex disease-causing network.
肌萎缩侧索硬化症（ALS）是一种罕见的进行性慢性运动神经元退行性疾病，目前尚无治愈方法。近年来，已鉴定出多个编码激酶和其他导致ALS的致病因子的基因。激酶是具有多效性的酶，可调节不同的信号转导过程和途径。激酶活性的失调会导致生理过程发生巨大变化，并引发包括癌症在内的许多其他人类疾病。
在本研究中，我们采用基于网络的系统生物学方法来研究ALS与其他人类疾病之间基于激酶的分子相互作用。首先确定了62种与ALS相关的激酶列表，然后通过扫描多个疾病-基因相互作用数据库来确定与它们相关的疾病，以了解与ALS相关的激酶与其他疾病之间的联系。
构建了一个包含36种激酶和与之相关的381种不同疾病的相互作用网络，这代表了与这些激酶相关的复杂性和共病性。此外，我们在致病网络中鉴定出了5种靶向大多数激酶的微小RNA（miRNA）。对这些miRNA进行了基因本体论和通路富集分析，以了解它们的生物学和分子功能，并确定重要的通路。我们还通过药物重新利用鉴定出了3种可干扰致病网络的药物分子。
本文提出的基于网络的研究有助于更好地了解与ALS疾病相关激酶的共病性的分子基础，并提供了破坏高度复杂致病网络的潜在治疗靶点。
