Amyotrophic lateral sclerosis: an update on recent genetic insights

J Neurol. 2013 Nov;260(11):2917-27. doi: 10.1007/s00415-013-7112-y. Epub 2013 Oct 2.

Abstract

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease affecting both upper and lower motor neurons. The prognosis for ALS is extremely poor, but there is a limited course of treatment with only one approved medication. A most striking recent discovery is that TDP-43 is identified as a key molecule that is associated with both sporadic and familial forms of ALS. TDP-43 is not only a pathological hallmark, but also a genetic cause for ALS. Subsequently, a number of ALS-causative genes have been found. Above all, the RNA-binding protein, such as FUS, TAF15, EWSR1 and hnRNPA1, have structural and functional similarities to TDP-43, and physiological functions of some molecules, including VCP, UBQLN2, OPTN, FIG4 and SQSTM1, are involved in a protein degradation system. These discoveries provide valuable insight into the pathogenesis of ALS, and open doors for developing an effective disease-modifying therapy.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Adenosine Triphosphatases / genetics
  • Amyotrophic Lateral Sclerosis / genetics*
  • Animals
  • Ataxins
  • Autophagy-Related Proteins
  • C9orf72 Protein
  • Cell Cycle Proteins / genetics
  • D-Amino-Acid Oxidase / genetics
  • DNA-Binding Proteins / genetics
  • Flavoproteins / genetics
  • Genetic Predisposition to Disease / genetics*
  • Humans
  • Membrane Transport Proteins
  • Mice
  • Mutation / genetics
  • Nerve Tissue Proteins / genetics
  • Phosphoric Monoester Hydrolases
  • Profilins / genetics
  • Proteins / genetics
  • RNA-Binding Protein FUS / genetics
  • Receptors, sigma / genetics
  • Sigma-1 Receptor
  • Transcription Factor TFIIIA / genetics
  • Ubiquitins / genetics
  • Valosin Containing Protein

Substances

  • Adaptor Proteins, Signal Transducing
  • Ataxins
  • Autophagy-Related Proteins
  • C9orf72 Protein
  • C9orf72 protein, human
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Flavoproteins
  • Membrane Transport Proteins
  • Nerve Tissue Proteins
  • OPTN protein, human
  • PFN1 protein, human
  • Profilins
  • Proteins
  • RNA-Binding Protein FUS
  • Receptors, sigma
  • SPG11 protein, human
  • Transcription Factor TFIIIA
  • UBQLN2 protein, human
  • Ubiquitins
  • DAO protein, human
  • D-Amino-Acid Oxidase
  • FIG4 protein, human
  • Phosphoric Monoester Hydrolases
  • Adenosine Triphosphatases
  • VCP protein, human
  • Valosin Containing Protein
  • Vcp protein, mouse