Pathogenic determinants and mechanisms of ALS/FTD linked to hexanucleotide repeat expansions in the C9orf72 gene

Neurosci Lett. 2017 Jan 1;636:16-26. doi: 10.1016/j.neulet.2016.09.007. Epub 2016 Sep 13.

Abstract

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two apparently distinct neurodegenerative diseases, the former characterized by selective loss of motor neurons in the brain and spinal cord and the latter characterized by selective atrophy of frontal and temporal lobes. Over the years, however, growing evidence from clinical, pathological and genetic findings has suggested that ALS and FTD belong to the same clinic-pathological spectrum disorder. This concept has been further supported by the identification of the most common genetic cause for both diseases, an aberrantly expanded hexanucleotide repeat GGGGCC/ CCCCGG sequence located in a non-coding region of the gene C9orf72. Three hypotheses have been proposed to explain how this repeats expansion causes diseases: 1) C9orf72 haploinsufficiency-expanded repeats interfere with transcription or translation of the gene, leading to decreased expression of the C9orf72 protein; 2) RNA gain of function-RNA foci formed by sense and antisense transcripts of expanded repeats interact and sequester essential RNA binding proteins, causing neurotoxicity; 3) Repeat associated non-ATG initiated (RAN) translation of expanded sense GGGGCC and antisense CCCCGG repeats produces potential toxic dipeptide repeat protein (DPR). In this review, we assess current evidence supporting or arguing against each proposed mechanism in C9 ALS/FTD disease pathogenesis. Additionally, controversial findings are also discussed. Lastly, we discuss the possibility that the three pathogenic mechanisms are not mutually exclusive and all three might be involved in disease.

Keywords: ALS; C9orf72; Dipeptide repeat protein; FTD; RNA foci; Repeat expansion disease.

Publication types

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

MeSH terms

  • Amyotrophic Lateral Sclerosis / genetics
  • Amyotrophic Lateral Sclerosis / metabolism*
  • Amyotrophic Lateral Sclerosis / pathology
  • Animals
  • C9orf72 Protein
  • DNA Repeat Expansion*
  • Frontotemporal Dementia / genetics
  • Frontotemporal Dementia / metabolism*
  • Frontotemporal Dementia / pathology
  • Haploinsufficiency
  • Humans
  • Mutation
  • Protein Biosynthesis
  • Proteins / genetics*
  • Proteins / metabolism

Substances

  • C9orf72 Protein
  • C9orf72 protein, human
  • Proteins