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C9orf72 isoforms in Amyotrophic Lateral Sclerosis and Frontotemporal Lobar Degeneration

Shangxi Xiao1, Laura MacNair2, Jesse McLean1

  • 1Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Canada.

Brain Research
|May 3, 2016
PubMed

Insights

The C9orf72 gene's hexanucleotide repeat expansion causes ALS and FTD. This review explores C9orf72's normal function and how its altered expression contributes to neurodegenerative disease pathogenesis.

Area of Science:

  • Neuroscience
  • Genetics
  • Molecular Biology

Background:

  • The C9orf72 gene hexanucleotide repeat expansion is the leading genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD).
  • Proposed toxic mechanisms include RNA foci, dipeptide repeat proteins, and C9orf72 haploinsufficiency.
  • While gain-of-function mechanisms are studied, the normal function of C9orf72 and consequences of its perturbation remain less understood.

Purpose of the Study:

  • To review current knowledge of C9orf72 at transcript and protein levels.
  • To explore how altered C9orf72 expression contributes to neurodegenerative disease pathogenesis.
  • To highlight the knowledge gaps concerning C9orf72's normal function.

Main Methods:

  • Literature review of studies on C9orf72.
  • Analysis of C9orf72 transcript and protein expression.
  • Discussion of proposed toxic gain-of-function and loss-of-function mechanisms.
  • Integration of findings within the context of RNA metabolism in disease.

Main Results:

  • C9orf72's role in disease is linked to repeat expansions, RNA foci, dipeptide proteins, and haploinsufficiency.
  • Significant knowledge gaps exist regarding C9orf72's normal cellular functions.
  • Understanding C9orf72's physiological roles is crucial for elucidating disease mechanisms.

Conclusions:

  • Further research into C9orf72's normal function is essential.
  • Elucidating C9orf72's cellular roles will advance understanding of ALS and FTLD.
  • This review synthesizes current knowledge on C9orf72 in neurodegeneration and RNA metabolism.
Keywords:
ALS/FTLDC9-isoformsC9-transcriptsC9orf72Hexanucleotide repeat expansion

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