The Regulatory Machinery of Neurodegeneration in In Vitro Models of Amyotrophic Lateral Sclerosis

Cell Rep. 2015 Jul 14;12(2):335-45. doi: 10.1016/j.celrep.2015.06.019. Epub 2015 Jul 2.


Neurodegenerative phenotypes reflect complex, time-dependent molecular processes whose elucidation may reveal neuronal class-specific therapeutic targets. The current focus in neurodegeneration has been on individual genes and pathways. In contrast, we assembled a genome-wide regulatory model (henceforth, "interactome"), whose unbiased interrogation revealed 23 candidate causal master regulators of neurodegeneration in an in vitro model of amyotrophic lateral sclerosis (ALS), characterized by a loss of spinal motor neurons (MNs). Of these, eight were confirmed as specific MN death drivers in our model of familial ALS, including NF-κB, which has long been considered a pro-survival factor. Through an extensive array of molecular, pharmacological, and biochemical approaches, we have confirmed that neuronal NF-κB drives the degeneration of MNs in both familial and sporadic models of ALS, thus providing proof of principle that regulatory network analysis is a valuable tool for studying cell-specific mechanisms of neurodegeneration.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amyotrophic Lateral Sclerosis / metabolism
  • Amyotrophic Lateral Sclerosis / pathology
  • Animals
  • Apoptosis / drug effects
  • Astrocytes / cytology
  • Astrocytes / metabolism
  • Cells, Cultured
  • Culture Media, Conditioned / pharmacology
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Humans
  • Mice
  • Mice, Transgenic
  • Models, Biological*
  • Motor Neurons / cytology
  • Motor Neurons / drug effects
  • Motor Neurons / metabolism*
  • Mutation
  • NF-kappa B / metabolism*
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Superoxide Dismutase / antagonists & inhibitors
  • Superoxide Dismutase / genetics
  • Superoxide Dismutase / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transcriptome / drug effects


  • Culture Media, Conditioned
  • Homeodomain Proteins
  • NF-kappa B
  • RNA, Small Interfering
  • Transcription Factors
  • Hb9 protein, mouse
  • Superoxide Dismutase

Associated data

  • GEO/GSE49023