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

• Published in: Cell Vol. 142; no. 4; pp. 601 - 612
• Main Authors: van Ham, Tjakko J., Holmberg, Mats A., van der Goot, Annemieke T., Teuling, Eva, Garcia-Arencibia, Moises, Kim, Hyun-eui, Du, Deguo, Thijssen, Karen L., Wiersma, Marit, Burggraaff, Rogier, van Bergeijk, Petra, van Rheenen, Jeroen, Jerre van Veluw, G., Hofstra, Robert M.W., Rubinsztein, David C., Nollen, Ellen A.A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 20.08.2010
• Subjects: alpha-Synuclein - metabolism; Amyloid beta-Peptides - metabolism; Animals; Caenorhabditis elegans - metabolism; Caenorhabditis elegans Proteins - chemistry; Caenorhabditis elegans Proteins - metabolism; Cell Line; Cell Line, Tumor; CELLBIO; Cellular Senescence; Humans; Mice; MOLNEURO; Nerve Tissue Proteins - chemistry; Nerve Tissue Proteins - metabolism; Neurodegenerative Diseases - metabolism; Peptides - metabolism; Proteins - chemistry; Proteins - metabolism; CELLBIO; MOLNEURO
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2010.07.020

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. [Display omitted] ► MOAG-4 promotes aggregation of aggregation-prone disease proteins ► Inactivation of MOAG-4 suppresses age-related proteotoxicity ► MOAG-4 regulates proteotoxicity independently of HSF-1 and DAF-16 ► The role of MOAG-4 is evolutionarily conserved in human SERF1A and SERF2