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.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid beta-Peptides / metabolism
  • Animals
  • Caenorhabditis elegans / metabolism*
  • Caenorhabditis elegans Proteins / chemistry
  • Caenorhabditis elegans Proteins / metabolism*
  • Cell Line
  • Cell Line, Tumor
  • Cellular Senescence*
  • Humans
  • Mice
  • Nerve Tissue Proteins / chemistry
  • Nerve Tissue Proteins / metabolism*
  • Neurodegenerative Diseases / metabolism*
  • Peptides / metabolism
  • Proteins / chemistry
  • Proteins / metabolism*
  • alpha-Synuclein / metabolism

Substances

  • Amyloid beta-Peptides
  • Caenorhabditis elegans Proteins
  • MOAG-4 protein, C elegans
  • Nerve Tissue Proteins
  • Peptides
  • Proteins
  • SERF1A protein, human
  • SERF2 protein, human
  • alpha-Synuclein
  • polyglutamine