Identification and therapeutic rescue of autophagosome and glutamate receptor defects in C9ORF72 and sporadic ALS neurons

JCI Insight. 2019 Jul 16;5(15):e127736. doi: 10.1172/jci.insight.127736.


Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease with diverse etiologies. Therefore, the identification of common disease mechanisms and therapeutics targeting these mechanisms could dramatically improve clinical outcomes. To this end, we developed induced motor neuron (iMN) models from C9ORF72 and sporadic ALS (sALS) patients to identify targets that are effective against these types of cases, which together comprise ~90% of patients. We find that iMNs from C9ORF72 and several sporadic ALS patients share two common defects - impaired autophagosome formation and the aberrant accumulation of glutamate receptors. Moreover, we show that an anticoagulation-deficient form of activated protein C, 3K3A-APC, rescues these defects in both C9ORF72 and sporadic ALS iMNs. As a result, 3K3A-APC treatment lowers C9ORF72 dipeptide repeat protein (DPR) levels, restores nuclear TDP-43 localization, and rescues the survival of both C9ORF72 and sporadic ALS iMNs. Importantly, 3K3A-APC also lowers glutamate receptor levels and rescues proteostasis in vivo in C9ORF72 gain- and loss-of-function mouse models. Thus, motor neurons from C9ORF72 and at least a subset of sporadic ALS patients share common, early defects in autophagosome formation and glutamate receptor homeostasis and a single therapeutic approach may be efficacious against these disease processes.

Keywords: ALS; Neurodegeneration; Neuroscience; Stem cells.

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

  • Adult
  • Aged
  • Amyotrophic Lateral Sclerosis / drug therapy*
  • Amyotrophic Lateral Sclerosis / genetics
  • Amyotrophic Lateral Sclerosis / immunology
  • Amyotrophic Lateral Sclerosis / pathology
  • Animals
  • Autophagosomes / drug effects*
  • Autophagosomes / immunology
  • Autophagy / genetics
  • C9orf72 Protein / genetics
  • C9orf72 Protein / metabolism
  • CHO Cells
  • Cells, Cultured
  • Cricetulus
  • Disease Models, Animal
  • Female
  • Gain of Function Mutation
  • Humans
  • Induced Pluripotent Stem Cells
  • Loss of Function Mutation
  • Lymphocytes
  • Male
  • Mice
  • Middle Aged
  • Motor Neurons / drug effects*
  • Motor Neurons / immunology
  • Motor Neurons / pathology
  • Primary Cell Culture
  • Protein C / administration & dosage*
  • Protein C / genetics
  • Proteostasis / drug effects
  • Proteostasis / immunology
  • Receptor, PAR-1 / agonists
  • Receptor, PAR-1 / metabolism
  • Receptors, Glutamate / metabolism
  • Recombinant Proteins / administration & dosage
  • Recombinant Proteins / genetics


  • C9orf72 Protein
  • C9orf72 protein, human
  • C9orf72 protein, mouse
  • Protein C
  • Receptor, PAR-1
  • Receptors, Glutamate
  • Recombinant Proteins