title: Identification of MOAG-4/SERF as a regulator of age-related proteotoxicity.
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.
authors: Department of Genetics, University Medical Centre Groningen, University of Groningen, Hanzeplein 1, 9700 RB Groningen, the Netherlands.
authors: Tjakko J
authors: TJ
authors: van Ham
authors: Mats A
authors: MA
authors: Holmberg
authors: Annemieke T
authors: AT
authors: van der Goot
authors: Eva
authors: E
authors: Teuling
authors: Moises
authors: M
authors: Garcia-Arencibia
authors: Hyun-eui
authors: HE
authors: Kim
authors: Deguo
authors: D
authors: Du
authors: Karen L
authors: KL
authors: Thijssen
authors: Marit
authors: M
authors: Wiersma
authors: Rogier
authors: R
authors: Burggraaff
authors: Petra
authors: P
authors: van Bergeijk
authors: Jeroen
authors: J
authors: van Rheenen
authors: G
authors: G
authors: Jerre van Veluw
authors: Robert M W
authors: RM
authors: Hofstra
authors: David C
authors: DC
authors: Rubinsztein
authors: Ellen A A
authors: EA
authors: Nollen
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D017173:Caenorhabditis elegans / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000737:chemistry / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D016922:Cellular Senescence; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism; D011506:Proteins / Q000737:chemistry / Q000378:metabolism*; D051844:alpha-Synuclein / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D029742:Caenorhabditis elegans Proteins; D047908:Intracellular Signaling Peptides and Proteins; C552054:MOAG-4 protein, C elegans; D009419:Nerve Tissue Proteins; D010455:Peptides; D011506:Proteins; C114841:SERF1A protein, human; C552053:SERF2 protein, human; D051844:alpha-Synuclein; C097188:polyglutamine