title: The essential and downstream common proteins of amyotrophic lateral sclerosis: A protein-protein interaction network analysis.
abstract: Amyotrophic Lateral Sclerosis (ALS) is a devastative neurodegenerative disease characterized by selective loss of motoneurons. While several breakthroughs have been made in identifying ALS genetic defects, the detailed molecular mechanisms are still unclear. These genetic defects involve in numerous biological processes, which converge to a common destiny: motoneuron degeneration. In addition, the common comorbid Frontotemporal Dementia (FTD) further complicates the investigation of ALS etiology. In this study, we aimed to explore the protein-protein interaction network built on known ALS-causative genes to identify essential proteins and common downstream proteins between classical ALS and ALS+FTD (classical ALS + ALS/FTD) groups. The results suggest that classical ALS and ALS+FTD share similar essential protein set (VCP, FUS, TDP-43 and hnRNPA1) but have distinctive functional enrichment profiles. Thus, disruptions to these essential proteins might cause motoneuron susceptible to cellular stresses and eventually vulnerable to proteinopathies. Moreover, we identified a common downstream protein, ubiquitin-C, extensively interconnected with ALS-causative proteins (22 out of 24) which was not linked to ALS previously. Our in silico approach provides the computational background for identifying ALS therapeutic targets, and points out the potential downstream common ground of ALS-causative mutations.
authors.affiliation: Applied Science Institute, Jiangxi University of Science and Technology, Jiangxi, China.|Department of Physiology, Northwestern University, Chicago, Illinois, United States of America.
authors.forename: Yimin
authors.initials: Y
authors.lastname: Mao
authors.affiliation: Department of Physiology, Northwestern University, Chicago, Illinois, United States of America.
authors.forename: Su-Wei
authors.initials: SW
authors.lastname: Kuo
authors.affiliation: Applied Science Institute, Jiangxi University of Science and Technology, Jiangxi, China.
authors.forename: Le
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Physiology, Northwestern University, Chicago, Illinois, United States of America.|Department of Physical Medicine and Rehabilitation, Northwestern University, Chicago, Illinois, United States of America.|Department of Physical Therapy and Human Movement Sciences, Northwestern University, Chicago, Illinois, United States of America.
authors.forename: C J
authors.initials: CJ
authors.lastname: Heckman
authors.affiliation: Department of Physiology, Northwestern University, Chicago, Illinois, United States of America.
authors.forename: M C
authors.identifier: http://orcid.org/0000-0002-8526-6830
authors.initials: MC
authors.lastname: Jiang
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism; D000465:Algorithms; D000690:Amyotrophic Lateral Sclerosis / Q000150:complications* / Q000235:genetics / Q000473:pathology; D018797:Cell Cycle Proteins / Q000378:metabolism; D016000:Cluster Analysis; D004268:DNA-Binding Proteins / Q000378:metabolism; D016208:Databases, Factual; D057180:Frontotemporal Dementia / Q000150:complications / Q000235:genetics / Q000473:pathology; D000076245:Heterogeneous Nuclear Ribonucleoprotein A1; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B / Q000378:metabolism; D006801:Humans; D010641:Phenotype; D060066:Protein Interaction Maps / Q000235:genetics*; D034702:RNA-Binding Protein FUS / Q000378:metabolism; D000074405:Valosin Containing Protein
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D000076245:Heterogeneous Nuclear Ribonucleoprotein A1; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; D034702:RNA-Binding Protein FUS; C000598624:TARDBP protein, human; C000619656:hnRNPA1 protein, human; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein