title: Molecular network analysis suggests a logical hypothesis for the pathological role of c9orf72 in amyotrophic lateral sclerosis/frontotemporal dementia.
abstract: BACKGROUND
  Expanded GGGGCC hexanucleotide repeats, ranging from hundreds to thousands in number, located in the noncoding region of the chromosome 9 open reading frame 72 (C9orf72) gene represent the most common genetic abnormality for familial and sporadic amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (abbreviated as C9ALS). Currently, three pathological mechanisms, such as haplo insufficiency of C9orf72, formation of nuclear RNA foci composed of sense and antisense repeats, and accumulation of unconventionally transcribed dipeptide-repeat (DPR) proteins, are proposed for C9ALS. However, at present, the central mechanism underlying neurodegeneration in C9ALS remains largely unknown.
  
  
  METHODS
  By using three distinct pathway analysis tools of bioinformatics, we studied molecular networks involved in C9ALS pathology by focusing on C9orf72 omics datasets, such as proteome of C9orf72 repeat RNA-binding proteins, transcriptome of induced pluripotent stem cells (iPSC)-derived motor neurons of patients with C9ALS, and transcriptome of purified motor neurons of patients with C9ALS.
  
  
  RESULTS
  We found that C9orf72 repeat RNA-binding proteins play a crucial role in the regulation of post-transcriptional RNA processing. The expression of a wide range of extracellular matrix proteins and matrix metalloproteinases was reduced in iPSC-derived motor neurons of patients with C9ALS. The regulation of RNA processing and cytoskeletal dynamics is disturbed in motor neurons of patients with C9ALS in vivo.
  
  
  CONCLUSIONS
  Bioinformatics data mining approach suggests a logical hypothesis that C9orf72 repeat expansions that deregulate post-transcriptional RNA processing disturb the homeostasis of cytoskeletal dynamics and remodeling of extracellular matrix, leading to degeneration of stress-vulnerable neurons in the brain and spinal cord of patients with C9ALS.
authors.affiliation: Department of Bioinformatics and Molecular Neuropathology, Meiji Pharmaceutical University, Kiyose, Tokyo, Japan.
authors.forename: Jun-Ichi
authors.initials: J
authors.lastname: Satoh
authors.affiliation: Department of Bioinformatics and Molecular Neuropathology, Meiji Pharmaceutical University, Kiyose, Tokyo, Japan.
authors.forename: Yoji
authors.initials: Y
authors.lastname: Yamamoto
authors.affiliation: Department of Bioinformatics and Molecular Neuropathology, Meiji Pharmaceutical University, Kiyose, Tokyo, Japan.
authors.forename: Shouta
authors.initials: S
authors.lastname: Kitano
authors.affiliation: Department of Bioinformatics and Molecular Neuropathology, Meiji Pharmaceutical University, Kiyose, Tokyo, Japan.
authors.forename: Mika
authors.initials: M
authors.lastname: Takitani
authors.affiliation: Department of Bioinformatics and Molecular Neuropathology, Meiji Pharmaceutical University, Kiyose, Tokyo, Japan.
authors.forename: Naohiro
authors.initials: N
authors.lastname: Asahina
authors.affiliation: Department of Bioinformatics and Molecular Neuropathology, Meiji Pharmaceutical University, Kiyose, Tokyo, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kino
keywords: C9orf72; KeyMolnet; amyotrophic lateral sclerosis; bioinformatics; frontotemporal dementia; molecular network; omics