RNA Toxicity From the ALS/FTD C9ORF72 Expansion Is Mitigated by Antisense Intervention

Neuron. 2013 Oct 16;80(2):415-28. doi: 10.1016/j.neuron.2013.10.015.

Abstract

A hexanucleotide GGGGCC repeat expansion in the noncoding region of the C9ORF72 gene is the most common genetic abnormality in familial and sporadic amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The function of the C9ORF72 protein is unknown, as is the mechanism by which the repeat expansion could cause disease. Induced pluripotent stem cell (iPSC)-differentiated neurons from C9ORF72 ALS patients revealed disease-specific (1) intranuclear GGGGCCexp RNA foci, (2) dysregulated gene expression, (3) sequestration of GGGGCCexp RNA binding protein ADARB2, and (4) susceptibility to excitotoxicity. These pathological and pathogenic characteristics were confirmed in ALS brain and were mitigated with antisense oligonucleotide (ASO) therapeutics to the C9ORF72 transcript or repeat expansion despite the presence of repeat-associated non-ATG translation (RAN) products. These data indicate a toxic RNA gain-of-function mechanism as a cause of C9ORF72 ALS and provide candidate antisense therapeutics and candidate human pharmacodynamic markers for therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Deaminase / metabolism
  • Amyotrophic Lateral Sclerosis / drug therapy
  • Amyotrophic Lateral Sclerosis / genetics
  • Amyotrophic Lateral Sclerosis / metabolism*
  • C9orf72 Protein
  • Cell Count
  • Dose-Response Relationship, Drug
  • Frontotemporal Dementia / drug therapy
  • Frontotemporal Dementia / genetics
  • Frontotemporal Dementia / metabolism*
  • Glutamic Acid / toxicity
  • Humans
  • Induced Pluripotent Stem Cells
  • Neurons / drug effects
  • Neurons / metabolism
  • Oligonucleotides, Antisense / pharmacology
  • Oligonucleotides, Antisense / therapeutic use*
  • Proteins / genetics
  • Proteins / metabolism*
  • RNA / genetics
  • RNA / metabolism
  • RNA / toxicity*
  • RNA-Binding Proteins
  • Repetitive Sequences, Nucleic Acid

Substances

  • C9orf72 Protein
  • C9orf72 protein, human
  • Oligonucleotides, Antisense
  • Proteins
  • RNA-Binding Proteins
  • Glutamic Acid
  • RNA
  • ADARB1 protein, human
  • Adenosine Deaminase