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RNA dysfunction and aggrephagy at the centre of an amyotrophic lateral sclerosis/frontotemporal dementia disease continuum

Matthew Thomas, Javier Alegre-Abarrategui, Richard Wade-Martins
DOI: http://dx.doi.org/10.1093/brain/awt030 First published online: 9 March 2013

Summary

Amyotrophic lateral sclerosis and frontotemporal dementia form two poles of a genetically, pathologically and clinically-related disease continuum. Analysis of the genes and proteins at the heart of this continuum highlights dysfunction of RNA processing and aggrephagy as crucial disease-associated pathways. TAR DNA binding protein and fused in sarcoma (FUS) are both RNA processing proteins whose dysfunction impacts on global cellular RNA regulation. The recent discovery that expression of repeat expansions in the C9orf72 gene may induce RNA foci that could sequester RNA binding proteins such as TAR DNA binding protein and FUS highlights a further possibly important mechanism of RNA dysfunction in disease. Furthermore, sequestration of key RNA binding proteins may also play an important role in sporadic disease due to the association of TAR DNA binding protein and FUS with stress granules. In a further functional convergence, ubiquilin 2, p62, valosin-containing protein and optineurin are all linked to aggrephagy, a cargo-specific subtype of autophagy important for degrading ubiquitinated target proteins through the lysosome. Notably these two key pathways interact; TAR DNA binding protein and FUS bind and regulate key aggrephagy-related genes whereas dysfunction of aggrephagy leads to cytoplasmic relocalization and aggregation of TAR DNA binding protein. The convergence of amyotrophic lateral sclerosis and frontotemporal dementia linked genes into these two pathways highlights RNA dysfunction and aggrephagy as promising areas for drug discovery. In this review we discuss the importance of each of these pathways and suggest mechanisms by which they may cause both sporadic and familial disease.

  • amyotrophic lateral sclerosis
  • frontotemporal dementia
  • RNA processing proteins
  • C9orf72
  • aggrephagy
  • Abbreviations
    ALS
    amyotrophic lateral sclerosis
    FTD
    frontotemporal dementia
    FTLD
    frontotemporal lobar degeneration
    TDP-43
    TAR DNA binding protein
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