Identification of MOAG-4/SERF as a regulator of age-related proteotoxicity

  • Cell. 2010 Aug 20;142(4):601-12. doi: 10.1016/j.cell.2010.07.020.
Tjakko J van Ham  1 ,  Mats A Holmberg ,  Annemieke T van der Goot ,  Eva Teuling ,  Moises Garcia-Arencibia ,  Hyun-eui Kim ,  Deguo Du ,  Karen L Thijssen ,  Marit Wiersma ,  Rogier Burggraaff ,  Petra van Bergeijk ,  Jeroen van Rheenen ,  G Jerre van Veluw ,  Robert M W Hofstra ,  David C Rubinsztein ,  Ellen A A Nollen
Affiliations
  • 1. Department of Genetics, University Medical Centre Groningen, University of Groningen, Hanzeplein 1, 9700 RB Groningen, the Netherlands.
PMID: 20723760 DOI: 10.1016/j.cell.2010.07.020
Abstract

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-beta in Alzheimer's Disease and alpha-synuclein in Parkinson's Disease. It is, however, poorly understood how these aggregates are formed during cellular aging. Here we identify an evolutionarily highly conserved modifier of aggregation, MOAG-4, as a positive regulator of aggregate formation in C. elegans models for polyglutamine diseases. 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-beta and alpha-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. 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.