Author/Authors :
Tjakko J. van Ham، نويسنده , , Mats A. Holmberg، نويسنده , , Annemieke T. van der Goot، نويسنده , , Eva Teuling، نويسنده , , Moises Garcia-Arencibia، نويسنده , , Hyun-eui Kim، نويسنده , , Deguo Du، نويسنده , , Karen L. Thijssen، نويسنده , , Marit Wiersma، نويسنده , , Rogier Burggraaff، نويسنده , , Petra van Bergeijk، نويسنده , , Jeroen van Rheenen، نويسنده , , G. Jerre van Veluw، نويسنده , , Robert M.W. Hofstra، نويسنده , , David C. Rubinsztein، نويسنده , , Ellen A.A. Nollen، نويسنده ,
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 Alzheimerʹs disease and alpha-synuclein in Parkinsonʹs 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.
