Identification of MOAG-4/SERF as a Regulator of Age-Related Proteotoxicity

Tjakko J. van Ham, 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*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

74 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)601-612
Number of pages12
JournalCell
Volume142
Issue number4
DOIs
Publication statusPublished - 20-Aug-2010

Keywords

  • INCLUSION-BODY FORMATION
  • HEAT-SHOCK FACTOR
  • CAENORHABDITIS-ELEGANS
  • HUNTINGTONS-DISEASE
  • POLYGLUTAMINE EXPANSIONS
  • MOLECULAR CHAPERONES
  • PROTEIN-DEGRADATION
  • CELLULAR TOXICITY
  • MUTANT HUNTINGTIN
  • QUALITY-CONTROL

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