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Pathogenic mechanisms
A30 Identification of MOAG-4/SERF as a regulator of age related proteotoxicity
  1. R Burggraaff1,
  2. T van Ham1,
  3. M Holmberg1,
  4. A van der Goot1,
  5. E Teuling1,
  6. M Garcia-Arencibia2,
  7. H-E Kim3,
  8. D Du4,
  9. K Thijssen1,
  10. M Wiersma1,
  11. P van Bergeijk1,
  12. J van Rheenen1,
  13. J van Veluw1,
  14. R Hofstra1,
  15. D C Rubinsztein2,
  16. E Nollen1
  1. 1Department of Genetics, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands
  2. 2Cambridge Institute for Medical Research, Department of Medical Genetics, University of Cambridge Wellcome Trust/MRC Building, Addenbrooke's Hospital, Cambridge, UK
  3. 3The Salk Institute for Biological Studies, Molecular and Cell Biology Laboratory, La Jolla, California, USA
  4. 4Departments of Chemistry and Molecular and Experimental Medicine and The Skaggs Institute of Chemical Biology, The Scripps Research Institute, La Jolla, California, USA

Abstract

Background Fibrillar protein aggregates are the major pathological hallmark of several incurable, age related, neurodegenerative disorders. These aggregates typically contain aggregation prone pathogenic proteins, such as amyloid-β in Alzheimer's disease and α-synuclein in Parkinson's disease. It is, however, poorly understood how these aggregates are formed during cellular ageing.

Aims The aim of this study was to identify genes that regulate aggregation.

Methods In order to investigate this we performed a chemical mutagenesis screen in a C elegans model for polyglutamine diseases.

Results We have identified an evolutionarily highly conserved modifier of aggregation, MOAG-4, as a positive regulator of aggregate formation. Inactivation of MOAG-4 suppresses the formation of compact polyglutamine aggregation intermediates that are required for aggregate formation. The role of MOAG-4 in driving aggregation extends to amyloid-β and α-synuclein and is evolutionarily conserved in its human orthologs SERF1A and SERF2. MOAG-4/SERF appears to act independently from HSF-1-induced molecular chaperones, proteasomal degradation and autophagy.

Conclusions Our results suggest that MOAG-4/SERF regulates age related proteotoxicity through a previously unexplored pathway, which will open up new avenues for research on age related, neurodegenerative diseases.

  • Huntington's disease
  • Alzheimer's disease
  • Parkinson's disease
  • C elegans
  • MOAG-4
  • SERF
  • protein aggregation
  • proteotoxicity
  • neurodegeneration
  • protein quality control

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