Received: 30 May 2018 | Accepted: 10 August 2018 DOI: 10.1002/jcp.27330 ORIGINAL RESEARCH ARTICLE A comparative system‐level analysis of the neurodegenerative diseases Rasoul Godini 1 | Hossein Fallahi 1 | Esameil Ebrahimie 2,3,4,5 1 Department of Biology, School of Sciences, Razi University, Kermanshah, Iran 2 Dame Roma Mitchell Cancer Research Laboratories (DRMCRL), Adelaide Medical School, The University of Adelaide, Adelaide, Australia 3 Institute of Biotechnology, Shiraz University, Shiraz, Iran 4 Division of Information Technology, Engineering and the Environment, School of Information Technology and Mathematical Sciences, The University of South Australia, Adelaide, Australia 5 Molecular Biology and Biotechnology, School of Biological Sciences, Faculty of Science and Engineering, Flinders University, Adelaide, Australia Correspondence Hossein Fallahi, Department of Biology, School of Sciences, Razi University, Kermanshah 6714414676, Iran. Email: h.fallahi@razi.ac.ir Abstract Neurodegenerative diseases are disorders in the central nervous system with consequent progressive neurological symptoms including behavioral and cognitive disabilities. Alzheimer’s disease, amyotrophic lateral sclerosis, Huntington’s disease, Parkinson’s disease, multiple sclerosis, and schizophrenia are the most important and abundant neurodegenerative diseases that affect different parts of the brain. Detailed studies unveiled the molecular mechanisms and pathways affected in each of these disorders. The role of many genes has been documented in the onset and progression of each disease. Although many system‐level approaches have been used to understand the exact cause of these diseases, there is no comparative analysis in this regard. Despite all differences in the molecular basis of these diseases, overlapping symptoms might indicate the involvement of the similar pathways and processes. Here, we have applied a system biology approach to uncover many aspects of main neurodegenerative diseases using microarray data obtained from 118 cases of postmortem brain samples. Our analysis has identified key genes that might contribute to the status of diseases. We have also compared the involved biological process and pathway between different disease to find possible similar mechanisms that exist in all of them. We also predicted potentially important transcription factors in each disease and predicted the core gene regulatory networks. We have provided a list of possible new key regulators that could be further explored and also discussed the role of these hub genes. The results of this study would be useful to develop new diagnostic strategies and also to find new drug targets. KEYWORDS Differential expression, gene expression, hub genes, network analysis, neurodegenerative disease, protein–protein interaction, system‐level 1 | INTRODUCTION Neurodegenerative diseases are disorders in the central nervous system (CNS) with consequent progressive neurological symptoms including behavioral and cognitive disabilities. Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), Huntington’s disease (HD), Parkinson’s disease (PD), multiple sclerosis (MS), and schizophrenia (SZ) are the most important and abundant neurodegenerative diseases that affect different parts of brain (Sheikh, Haque, & Mir, 2013). As a result of different pathogenicity mechanisms, specific symptoms are associated with each of these diseases. Neurodegenerative diseases are the result of abnormalities in the genome and/or metabolism in brains. AD usually starts after the age of 60 and causes a gradual increase in the cognitive impairment and dementia. Neurofibrillary tangles and neurotic plaques are the main microscopic features of the AD, which deposit within the extra- cellular spaces of nerve cells (Henderson, 2014). ALS, on the other hand, is linked to the motor neurons in the brain and spinal cord, J Cell Physiol. 2018;1–15. wileyonlinelibrary.com/journal/jcp © 2018 Wiley Periodicals, Inc. | 1