Inherited and Sporadic Amyotrophic Lateral Sclerosis and Fronto-Temporal Lobar Degenerations arising from Pathological Condensates of Phase Separating Proteins

Hum Mol Genet. 2019 Nov 21;28(R2):R187-R196. doi: 10.1093/hmg/ddz162.

Abstract

Recent work on the biophysics of proteins with low complexity, intrinsically disordered domains that have the capacity to form biological condensates has profoundly altered the concepts about the pathogenesis of inherited and sporadic neurodegenerative disorders associated with pathological accumulation of these proteins. In the present review, we use the FUS, TDP-43 and A11 proteins as examples to illustrate how missense mutations and aberrant post-translational modifications of these proteins cause amyotrophic lateral sclerosis (ALS) and fronto-temporal lobar degeneration (FTLD).

Keywords: ANXA11; Amyotrophic lateral sclerosis; FUS; TDP-43; biological condensates; fronto-temporal dementia; gelation; hydrogels; local RNA translation; neuronal transport granules; phase separation; stress granules.

Publication types

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

MeSH terms

  • Amyotrophic Lateral Sclerosis / genetics*
  • Annexins / chemistry
  • Annexins / genetics*
  • Annexins / metabolism
  • Biological Transport / genetics
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Frontotemporal Lobar Degeneration / genetics*
  • Humans
  • Intracellular Membranes / chemistry
  • Intracellular Membranes / metabolism
  • Mutation, Missense
  • Neurodegenerative Diseases / physiopathology
  • Neurons / chemistry
  • Neurons / metabolism
  • Protein Processing, Post-Translational / genetics
  • RNA-Binding Protein FUS / chemistry*
  • RNA-Binding Protein FUS / genetics
  • RNA-Binding Protein FUS / metabolism
  • Temporal Lobe / physiopathology*

Substances

  • Annexins
  • DNA-Binding Proteins
  • RNA-Binding Protein FUS
  • TARDBP protein, human